Systems and methods for sensing and stimulation

Abstract

To provide improved systems and methods for sensing and stimulation.SOLUTION: A system for stimulating body tissue may include a stimulation lead, sensors, and a control unit. The stimulation lead may include one or more energy sources. The control unit may include a processor and non-transitory computer readable medium, and an interface (e.g., touch screen interface) for receiving user inputs and communicating information to the user. The sensors may be configured to provide impedance measurements to the control unit. The control unit may calculate lung gas distributions and / or generate an image modeling lung gas distributions. Stimulation delivered by the stimulation may be adjusted based on the impedance measurements.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] Embodiments of the present disclosure generally relate to methods and devices (including systems) for detecting and delivering stimuli. More specifically, the present disclosure relates to methods and systems for detecting nerves and / or muscles and delivering stimuli to nerves and / or muscles.

Background Art

[0002] Patients in a hospital's intensive care unit (ICU) have a reduced ability to breathe spontaneously due to the state of their underlying diseases, and in order to provide ventilation assistance, they may require positive pressure mechanical ventilation (PPMV) and / or other external respiratory support means (collectively referred to as ERS (External Respiratory Support)). In the ICU, ERS is often used in combination with sedatives to provide mandatory ventilation to these critically ill patients. Further, for example, many patients undergoing surgery under general anesthesia in a hospital's operating room (OR), or patients receiving treatments that require anesthesia or sedation in a hospital's emergency room (ER), generally require ERS for ventilation assistance while they are anesthetized or sedated.

[0003] Mechanical ventilation is a life support measure, but when combined with sedatives or anesthesia, it impedes the active contraction of the diaphragm. Prolonged and fully controlled mechanical ventilation can lead to a complete loss of neural activation and mechanical activity of the diaphragm, inducing muscle atrophy, proteolysis, and free radical release, resulting in a rapid loss of diaphragm function, a syndrome known as ventilator-induced diaphragmatic dysfunction (VIDD). These patients are also known to have a higher level of damage to the lungs, brain, heart, and other organs. These patients also have a higher risk of other co-morbidities, including infection and sepsis, and the risk of death increases with each additional day of ERS.

[0004] Approximately 15 million ICU patients per year require mechanical ventilation. Furthermore, about one-third of these patients require a long-term weaning to overcome dependence on the ventilator. Most patients who require diaphragmatic weaning exhibit atrophy and dysfunction of the diaphragm. Generally, patients who require mechanical ventilation are at risk of prolonged ICU / hospital stays, high medical costs, poor long-term functional outcomes, and increased respiratory complications and mortality.

[0005] Most methods of ERS provide a gas exchange means different from natural breathing. When positive pressure ventilation is used, ventilator induced lung injury (VILI), which is a form of high-volume injury known as barotrauma and low-volume injury known as atelectasis, easily occurs. These unnatural breathing methods can lead to changes in the total amount of air provided to the patient's lungs and can also shift the distribution of air among various lung regions (e.g., front, back, left, right, upper, lower, etc.). The lung stretch receptors of patients receiving certain types of ERS such as positive pressure ventilation send abnormal signals to the brain that lead to inflammation and other processes affecting multiple organs, potentially inducing further damage such as ventilator induced brain injury (VIBI). The diaphragm muscle typically assists in the preload of venous blood returning to the heart, and since the high pressure of positive pressure ventilators increases chest pressure, the heart of MV (mechanical ventilation) patients with an inactive diaphragm is susceptible to damage from overwork. Patients are also more likely to have an increased incidence of ventilator-induced pneumonia and hospital-acquired infections (VAP) and sepsis.

[0006] The onset of VIDD, VILI, VAP, VIBI, and other ERS-induced injuries is rapid, delaying the patient's recovery, increasing the risk of further complications, prolonging ventilator dependence, lengthening ICU stays, increasing hospitalization costs, and increasing the risk of death with each additional day of mechanical ventilation.

Summary of the Invention

[0007] Embodiments of the present disclosure relate, inter alia, to systems, devices, and methods for providing respiratory assistance. Embodiments include applying a stimulus to one or more anatomical targets. Embodiments of the systems and methods described herein may be used in lieu of and / or in addition to mechanical ventilation (MV) and / or may incorporate external respiratory stimulation (ERS), such as, for example, stimulation of the respiratory nerves and / or respiratory muscles. Each embodiment disclosed herein may include one or more of the features described in relation to any of the other disclosed embodiments.

[0008] Embodiments of the present disclosure relate, inter alia, to systems, devices, and methods for applying a stimulus to tissue. Embodiments of the systems and methods described herein may be used in lieu of and / or in addition to external respiratory assistance, such as, for example, stimulation of the respiratory nerves and / or respiratory muscles. Each embodiment disclosed herein may include one or more of the features described in relation to any of the other disclosed embodiments.

[0009] In one example, a method of stimulating tissue may include delivering a first stimulus (which may include a first value of a stimulation parameter) to the tissue via a stimulation device, measuring the impedance of the lung tissue, determining, based on the impedance, a second value of a stimulation parameter of a second stimulus, the second value being different from the first value, and delivering the second stimulus to the tissue via the stimulation device.

[0010] Any of the methods disclosed herein may include any of the following features. The method may further include calculating a lung gas parameter based on impedance and / or comparing the lung gas parameter with a predetermined lung gas parameter. Determining the second value may include calculating the second value based on the lung gas parameter. The lung gas parameter may correspond to the air distribution between the posterior and anterior regions of the lung, the air distribution between the upper and lower regions of the lung, the air distribution between the left and right lungs, and / or one or more lung volumes. Delivering the first stimulus, delivering the second stimulus, or both may include delivering an electrical stimulus. Delivering the second stimulus may include delivering a stimulus to the phrenic nerve and / or delivering a stimulus that causes contraction of the respiratory muscles. The impedance may be measured by one or more sensors disposed on or within the patient. The stimulation device may include at least one electrode, and the method herein may include disposing the stimulation device within the patient such that at least one electrode is proximate to the phrenic nerve.

[0011] An exemplary method for stimulating tissue may include measuring bioelectrical impedance, determining a first value of a lung gas parameter based on the impedance, comparing the first value with a predetermined value of the lung gas parameter, determining one or more stimulation parameters based on the comparison of the first value and the predetermined value, and delivering a stimulation signal including the one or more stimulation parameters to the tissue. The lung gas parameter may correspond to the distribution of air between regions of the lung.

[0012] Any of the methods disclosed herein may include any of the following features. The method may further include determining a first lung volume before delivering a stimulation signal and determining a second lung volume after delivering the stimulation signal. Each of the first lung volume and the second lung volume may be the volume of the lower or anterior region of the lung. The stimulation parameters may include duration, pulse width, frequency, amplitude, or a combination thereof. The stimulation signal may be delivered via at least one electrode, and the bioelectrical impedance may be measured via at least one electrode. Comparing a first value of a lung gas parameter with a predetermined value may include comparing the first value with a range of predetermined values. Delivering the stimulation signal can cause contraction of the respiratory muscles. The bioelectrical impedance may be a first bioelectrical impedance, the stimulation signal may be a first stimulation signal, one or more stimulation parameters may be first stimulation parameters, and the method may include measuring a second bioelectrical impedance, determining a second value of a lung gas parameter based on the second bioelectrical impedance, comparing the second value with the first value or a predetermined value, and determining one or more second stimulation parameters and / or delivering a second stimulation including one or more second stimulation parameters based on the comparison of the second value with the first value or a predetermined value.

[0013] An exemplary system for stimulating tissue may include a stimulation device, an impedance sensor, and a control unit configured to receive an impedance signal from the impedance sensor, determine a first value of a lung gas parameter based on the impedance signal, where the lung gas parameter corresponds to the distribution of air between regions of the lung, compare the first value with a predetermined value of the lung gas parameter, determine one or more stimulation parameters based on the comparison of the first value with the predetermined value, and deliver a stimulation signal including the one or more stimulation parameters to the tissue via the stimulation device.

[0014] Any of the systems or methods disclosed herein may include any of the following features. The system may further include an external respiratory assistance device. The impedance sensor may be part of an array of impedance sensors, and the array may be configured to be attached to the exterior of a patient. The control unit may be further configured to generate an image corresponding to the distribution of air between regions of the lungs.

[0015] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate non-limiting embodiments of the disclosure and, together with the specification, serve to explain the principles of the disclosure.

Brief Description of the Drawings

[0016]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9A

Figure 9B

Figure 10A

Figure 10B

Figure 10C

Figure 10D

Figure 10E

Figure 10F

Figure 10G

Figure 10H

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17A

Figure 17B

Figure 18A

Figure 18B

Figure 18C

Figure 18D

Figure 19

Figure 20

Figure 21A

Figure 21B

Figure 22

Figure 23A

Figure 23B

Figure 23C

Figure 24A

Figure 24B

Figure 24C

Figure 25A

Figure 25B

Figure 26A

Figure 26B

Figure 26C

MODE FOR CARRYING OUT THE INVENTION

[0017] Phrenic nerve stimulation, diaphragm muscle pacing, and transcutaneous stimulation are thought to assist in the movement of a patient's respiratory muscles (e.g., diaphragm, intercostal, abdominal, etc.) and address the issues described above. Various systems and methods for sensing, stimulating, and / or providing respiratory assistance are described herein. It should be understood that any component, step or process of the described methods or components or elements of the described systems may be used in combination with other components, steps or processes of any of the methods described herein or components or elements of the systems.

[0018] Generally, all publications and patent applications mentioned herein are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent application were specifically indicated to be incorporated by reference. For example, embodiments of the present disclosure may be used in combination with one or more systems, catheters, devices, and electrodes described in U.S. Patent No. 8,571,662, U.S. Patent No. 9,242,088, U.S. Patent No. 9,333,363, U.S. Patent No. 9,776,005, U.S. Patent No. 10,039,920, U.S. Patent No. 10,293,164, U.S. Patent Application Publication No. 2015 / 0045810, U.S. Patent Application Publication No. 2019 / 0001126, U.S. Patent Application Publication No. 2019 / 0175908, U.S. Patent Application Publication No. 2019 / 0038894, and / or U.S. Patent Application Publication No. 2020 / 0147364. All of these disclosures are hereby incorporated by reference.

[0019] Throughout the following description, specific details are set forth to provide a thorough understanding by those skilled in the art. The following description of examples of the technology is not intended to be exhaustive or to limit the system to the precise form of any exemplary embodiment. Accordingly, the specification and drawings are to be interpreted in an illustrative rather than a limiting sense.

[0020] Different embodiments of various medical device components may be used in combination with one another in any logical configuration. Further, the individual features or elements of any described embodiment may be combined with or used with the individual features or elements of other embodiments. The various embodiments may further be used in situations different from those specifically described herein. For example, the disclosed electrode structures may be combined with or used in combination with various indwelling systems well known in the art for various diagnostic and / or therapeutic applications.

[0021] For the purposes of the present disclosure, respiratory muscles may mean any muscle that can contribute to or be involved in inspiration, expiration, coughing, or any other activity for the ingress and egress of air in a human. Generally, these muscles assist in the expansion and contraction / compression of the thoracic cavity, abdomen, or other areas related to breathing. Examples of respiratory muscles include the diaphragm, intercostal muscles, and accessory muscles (sternocleidomastoid muscle, scalene muscles (anterior, middle, and posterior scalene muscles)). Other exemplary respiratory muscles include the serratus anterior muscle, pectoralis major and minor muscles, mitral muscles, latissimus dorsi muscle, erector spinae muscles, lumbar iliocostalis muscle, quadratus lumborum muscle, superior posterior serratus muscle, inferior posterior serratus muscle, levatores costarum muscles, transversus thoracis muscle, levator labii superioris alaeque nasi muscle, and subclavius muscle. Other respiratory muscles such as those that support expiration include the abdominal wall muscles (rectus abdominis muscle, transversus abdominis muscle, external oblique muscle, and internal oblique muscle) and the internal intercostal muscles. The respiratory muscle stimulation systems and devices described herein may be used to activate any of these or other related respiratory muscles.

[0022] One or more of the methods described herein can induce contraction of respiratory muscles using electrical stimulation, for example, using an energy source such as electrodes that can be placed externally or internally to a patient. An external or implantable controller (e.g., a pacemaker-like device) may be used to manage the delivery of energy.

[0023] In some embodiments, the respiratory muscle stimulation device activates muscle contractions by stimulating one or more phrenic nerves. The two phrenic nerves that control the activation of the diaphragm run along the left and right sides of the heart within the thorax and then reach the diaphragm. Stimulation of the phrenic nerves can be performed by electrically stimulating one or both phrenic nerves to control the patient's respiratory muscles (e.g., the diaphragm and / or one or more other respiratory muscles). In some embodiments, stimulation of one or more phrenic nerves can induce a respiratory cycle.

[0024] In some embodiments, a minimally invasive device that is easy to arrange is designed to stimulate the patient's respiratory muscles, provide a more natural breathing method, reduce physical damage, and promote the patient's reacquisition of independent breathing.

[0025] In some embodiments, the device and system may include a respiratory muscle activation unit, a pulmonary gas distribution sensor, and a controller for adjusting the parameters of the muscle activation unit to improve / maintain an optimal gas balance within various regions of the patient's lungs.

[0026] In at least one embodiment, the respiratory therapy system can be configured to manage the distribution of gas (e.g., air) within the regions of the patient's lungs. The system may include a control unit, a stimulation array, and / or a plurality of impedance or other gas distribution (e.g., ultrasonic, MRI, CT, etc.) sensors. The control unit may be configured to manage the performance of the respiratory therapy system. Further, the control unit may be configured to receive a bioelectrical impedance or other gas distribution signal, analyze the bioelectrical impedance or gas distribution signal, determine pulmonary gas parameter values (e.g., the approximate air distribution between the posterior and anterior regions of the lungs, the air distribution between the left and right sides of the lungs, volume, and / or pressure), and / or compare the pulmonary gas parameter values with pulmonary gas parameter target values (e.g., preset values). The control unit may also be configured to adjust the stimulation parameters when the measured pulmonary gas parameter values deviate from the desired pulmonary gas parameter values.

[0027] The stimulation array may be configured to deliver energy by an energy source well-known in the art (e.g., electricity, ultrasonic, electromagnetic, etc.). The delivery of energy by the stimulation array can cause the contraction of respiratory muscles. The stimulation array may be functionally connected to a control unit. The stimulation array may include electrodes, electrodes disposed outside the subject, electrodes disposed inside the subject, or electrodes disposed outside the subject and electrodes disposed inside the subject. The stimulation array may include a linear array of electrodes or a two-dimensional array of electrodes. Additionally or alternatively, the stimulation may include an energy source other than electrodes (e.g., transducer, electromagnetic coil, laser, etc.). The stimulation array may include a catheter, a needle, and / or a percutaneous or subcutaneous lead, may be disposed on the catheter, the needle, and / or the percutaneous or subcutaneous lead, or may be electrically connected to the catheter, the needle, and / or the percutaneous or subcutaneous lead. The stimulation array may include an array for stimulating the respiratory muscles on the right side of the patient, an array for stimulating the respiratory muscles on the left side of the patient, or both. In some embodiments, the stimulation level of the array for stimulating the respiratory muscles on the right side of the patient and the stimulation level of the array for stimulating the respiratory muscles on the left side of the patient may be independently controlled.

[0028] A plurality of impedance or other gas distribution sensors may be configured to acquire bioelectrical impedance signals from the patient. The impedance sensor may be functionally connected to a control unit. The impedance sensor may include electrodes, electrodes disposed outside the subject, electrodes disposed inside the subject, or electrodes disposed outside the subject and electrodes disposed inside the subject. In some embodiments, at least one impedance sensor is disposed outside the subject and at least one impedance sensor is disposed subcutaneously in the subject. The impedance sensor may also be configured to stimulate the respiratory muscles. In some embodiments, the impedance sensor disposed inside the subject and the impedance sensor disposed outside the subject may transmit stimulation to control a part of the inhalation phase and the exhalation phase.

[0029] In some embodiments, the system may be configured to reduce signal transmission from pulmonary stretch receptors in order to reduce at least one of atelectasis, barotrauma, VILI, and / or VIBI. The system may further include an external positive pressure breathing device for delivering gas to the patient's lungs. The system may detect the operation of the positive pressure breathing device by a sensor or may be functionally connected to the positive pressure breathing device. In some embodiments, the controller can manage inputs from impedance sensors and external respiratory assistance devices and adjust the stimulation energy to improve the gas balance within the subject's lungs. The system may further include at least one physiological sensor functionally connected to the control unit for obtaining physiological data of the patient regarding at least one of tidal volume, lung volume (e.g., volume of a lung region), respiratory pressure, respiratory rate, work of breathing, CO2 saturation, oxygen saturation, body temperature, blood pressure, heart rate, blood oxygen concentration, movement, motion, and / or brain activity.

[0030] In some embodiments, the device and system may include a respiratory muscle activation unit, an external respiratory assistance device, a pulmonary gas distribution sensor, and / or a controller. The controller may be configured to adjust the parameters of the muscle activation unit and the external respiratory assistance device to improve / maintain a favorable gas balance within various regions of the patient's lungs during one or more respiratory cycles.

[0031] The device and system may be configured to manage the disruption of accumulated mucus, fluids, and other lung secretions. In some embodiments, the device and system may include a stimulation array for delivering energy. The energy delivered is designed to cause contraction of one or more respiratory muscles at frequencies, intensities, and specified waveforms that can expose, remove, disrupt, release, and / or transport accumulated mucus, fluids, and / or other secretions within the patient's lungs so that they can be easily removed from the patient.

[0032] In some embodiments, the devices and systems may be configured to open the lower / low / distal / posterior lung regions so that pooled mucus, fluids, and / or other secretions can be exposed, removed, disrupted, released, transported, and / or otherwise acted upon to be readily removed from the patient. In some aspects, the tidal volume of the patient may increase over time.

[0033] The removal of secretions and mucus from the lungs of healthy individuals is primarily achieved by the body's normal mucociliary action, coughing, and the spontaneous movement of an individual's body. Under physiologically sound conditions, these mechanisms efficiently remove and eliminate secretions, mucus, contaminants, and / or other fluid accumulations in the lungs (collectively referred to as respiratory secretions). Impairment of the normal mucociliary clearance system, periods of immobility or bed rest, or excessive secretion of respiratory mucus can lead to the accumulation of mucus and necrotic tissue fragments in the lungs. For patients receiving external respiratory assistance such as positive-pressure mechanical ventilation, this problem may be exacerbated because the pressure from the ventilator pushes secretions into the lower / posterior lung regions. This is because these lower lobe regions typically become deflated over time (e.g., atelectasis), trap secretions and harmful bacteria, and the patient's condition may be further complicated by the inability to cough.

[0034] Chest physiotherapy is often clinically effective and is typically part of standard medical practice to promote the removal / transport of respiratory mucus. Chest physiotherapy often includes mechanical manipulation of the chest, external vibration, and directed cough. Some have attempted to develop devices to mechanically remove accumulated lung secretions. However, as described above, the lower / posterior regions of many patients become deflated (e.g., atelectasis) and trap secretions, so standard techniques (e.g., those involving forced air or airway positive pressure) are not effective at disrupting or releasing these substances.

[0035] The respiratory muscle stimulation system described herein can be used to provide the additional advantage of opening the lower / posterior lung regions and releasing respiratory secretions. The secretolytic performance may be carried out at any time during the respiratory cycle (e.g., during inhalation, exhalation, etc.). By using stimulation of either or both the inspiratory and expiratory muscles or the abdominal muscles, these secretions can be released using coordinated contractions at a desired frequency. Depending on the patient's situation, the stimulation can be focused on one side versus the other side, e.g., the right side.

[0036] In one or more embodiments, a method of managing the removal of accumulated mucus and other respiratory secretions (e.g., using a respiratory therapy system) may include stimulating the inspiratory muscles (e.g., the diaphragm muscle) to contract at a frequency, intensity, and specified waveform suitable for opening the lower / posterior lung regions and exposing, removing, destroying, releasing, and / or transporting the accumulated respiratory secretions. After the respiratory secretions have been exposed, removed, destroyed, released, and / or transported, the respiratory secretions can be easily removed from the subject. The inspiratory muscles may be stimulated, for example, via a stimulation array configured to deliver energy. The stimulation array may be operatively connected to a control unit, which may be configured to manage the performance of the respiratory therapy system. The stimulation array may include an array for stimulating the respiratory muscles on the right side of the patient, an array for stimulating the respiratory muscles on the left side of the patient, or both. In some embodiments, the stimulation levels of the array for stimulating the respiratory muscles on the right side of the patient and the array for stimulating the respiratory muscles on the left side of the patient may be independently controlled.

[0037] In some embodiments, a method of managing the removal of accumulated mucus and other respiratory secretions (e.g., using a respiratory therapy system) may include increasing gas distribution in the lower / lower lungs during or after treatment. The tidal volume of respiration during or after treatment may be increased. The inspiratory muscles may be the diaphragm muscle and / or the intercostal muscles. The method may further include stimulating the expiratory muscles. In some embodiments, at least one impedance sensor is used to monitor regional lung gas distribution. The method may include using an airflow sensor, a pressure sensor, and / or a volume sensor. In some embodiments, the method further includes using an external positive pressure breathing device to deliver gas to the subject's lungs.

[0038] In some embodiments, a mechanically ventilated subject may be able to extubate earlier and / or have an increased tidal volume after movement of respiratory secretions. The respiratory therapy system used in the exemplary method may either be sensed by a sensor to operate the positive pressure breathing device or may be functionally connected to the positive pressure breathing device. The system may further include at least one physiological sensor functionally connected to a control unit for obtaining patient physiological data regarding at least one of tidal volume, lung volume (e.g., volume of a lung region), respiratory pressure, respiratory rate, work of breathing, CO2 saturation, oxygen saturation, body temperature, blood pressure, heart rate, blood oxygen concentration, and / or brain activity.

[0039] In some embodiments, a respiratory therapy system configured to manage the disruption of pooled mucus and other lung secretions may include a control unit, a stimulation array, and / or a stimulation algorithm for managing the performance of the respiratory therapy system. The stimulation array may be operably connected to the control unit, and the control unit may be configured to manage the performance of the respiratory therapy system. The stimulation array may include an array for stimulating the respiratory muscles on the right side of the patient, an array for stimulating the respiratory muscles on the left side of the patient, or both. In some embodiments, the stimulation levels of the array for stimulating the respiratory muscles on the right side of the patient and the array for stimulating the respiratory muscles on the left side of the patient may be independently controlled.

[0040] The stimulation algorithm may include one or more waveforms configured to activate the inspiratory muscles (e.g., diaphragm muscle, intercostal muscles, abdominal muscles, etc.) to contract at a frequency, intensity, and specified waveform to open the lower / posterior lung regions. The contraction of the inspiratory muscles can expose, remove, disrupt, release, and / or transport respiratory secretions so that they can be easily removed from the patient.

[0041] A respiratory therapy system configured to manage the disruption of pooled mucus and other lung secretions may further include an impedance or other lung sensor for determining lung function parameters. The controller may include an algorithm configured to receive data regarding the lung function parameters and communicate the lung function parameters to the user. In some embodiments, the controller can analyze the bioelectrical impedance signal and determine changes in the air distribution between the posterior and anterior regions of the lung. This determination can be communicated to the user.

[0042] In some embodiments, a minimally invasive device may be configured to stimulate the respiratory muscles of a patient. The device may include an array of energy emitters and an anchoring system for securing the device. The device may also be configured such that stimulation energy can be provided to the target nerves and / or one or more muscles over an extended period of time.

[0043] In some embodiments, the respiratory therapy system may include a control unit, one or more energy emitters, a delivery cannula, directing means, one or more anchors, and / or a sensor for determining lung gas parameters. The control unit may be configured to manage the performance of the respiratory system. The control unit may receive signals from the sensor, analyze the signals from the sensor, determine lung gas parameter values (e.g., approximate air distribution between the posterior and anterior regions of the lung, air distribution between the left and right sides of the lung, volume [e.g., tidal volume, regional lung volume, etc.], and / or pressure [e.g., MIP (maximal inspiratory pressure), MEP (maximal expiratory pressure), peak pressure, plateau pressure, pressure-time integral, etc.]), and / or compare the lung gas parameter values with lung gas parameter target values (e.g., preset values, calculated values, etc.). The control unit may also be configured to adjust the stimulation parameters if the measured lung gas parameter values deviate from the desired lung gas parameter values.

[0044] One or more energy emitters (e.g., a stimulation array) may be configured to deliver energy to cause contraction of the respiratory muscles. The one or more energy emitters may be operably connected to a control unit. A delivery cannula may be configured to guide one or more energy emitters (e.g., a stimulation array) to the target tissue. The delivery cannula may include an elongate cannula having at least one lumen or channel for receiving the one or more energy emitters. The delivery cannula may include one or more stimulation windows along the distal end of the cannula, from which energy for stimulating the target can be emitted. Directional means may contact the delivery cannula, the one or more energy emitters, or both the delivery cannula and the one or more energy emitters. The directional means may enable the energy emitter to be aligned with the window of the delivery cannula. One or more anchors may be coupled to the one or more energy emitters and may be configured to secure the one or more energy emitters at a tissue location proximate to the target tissue.

[0045] In some embodiments, a method for stimulating the respiratory nerves of a patient's body may include positioning a respiratory muscle stimulation device such that the distal end of the device (e.g., the lead body) is proximate to the target nerve and the proximal end of the stimulation device is external to the patient, supplying electrical energy to the distal end of the device to stimulate a portion of the target nerve, detecting a response resulting from the stimulation of the respiratory nerve, securing the lead to the patient to reduce movement of the lead, and supplying electrical energy to the distal end of the device to cause contraction of the respiratory muscles and / or contracting the respiratory muscles an appropriate number of times over at least two days. Such a method can increase respiratory muscle strength or reduce loss of muscle strength.

[0046] The method may include placing a delivery cannula, which comprises an elongate cannula having at least one lumen or channel for receiving one or more energy emitters. The delivery cannula may also include one or more stimulation windows along the distal end of the cannula, from which energy for stimulating a target may be emitted. The proximal end of the respiratory muscle stimulation device may include orientation means. The orientation means may be in contact with the delivery cannula, the lead body, one or more electrodes on the distal end of the respiratory muscle stimulation device, or a combination thereof. The orientation means can indicate a preferred orientation or position (e.g., left or right, up or down, distal or proximal, etc.) with respect to the patient's skin.

[0047] In some embodiments, the distal end of the device includes a flexible lead that includes a directional electrode. The directional electrode can generate an electric field. This electric field varies in intensity as a function of the circumferential angular position relative to the longitudinal axis of the flexible lead at a given longitudinal position and radial distance in the vicinity of the stimulation electrode. Placing the respiratory muscle stimulation device may include inserting the flexible lead through a separable cannula delivery system into the patient's body, removing the separable cannula delivery system from the patient's body, and creating a longitudinal channel or opening in the separable cannula delivery system so that the flexible lead can be separated from the separable cannula delivery system. In some embodiments, a portion of the lead body changes from a first compact geometric configuration (e.g., before placement in the body) to a second geometric configuration (e.g., after placement in the body). The second geometric configuration may not be as compact as the first geometric configuration.

[0048] In one or more embodiments, the system may include a transcutaneous lead that includes an energy source (e.g., an electrode that dissipates charge, or some other energy source that emits some form of energy including electricity, ultrasound, light, heat, or a chemical substance). The energy source may be electrically connected to at least one other energy source. The system may further include a control unit that communicates with the transcutaneous lead to manage the delivery of energy. The control unit may communicate with one or more sensors to control a desired result by varying the amount of energy delivered. One or more sensors (e.g., a nerve sensor, an O2 sensor, a CO2 sensor, a motion sensor, an airway flow sensor, an airway pressure sensor, an impedance sensor, an EIT (electrical impedance tomography) sensor, an EIS (electrical impedance scanning) sensor, an EMG (electromyography) sensor, an EEG (electroencephalogram) sensor, an EKG sensor, and / or a cognitive function sensor, etc.) can provide feedback to the control unit regarding the patient's physiological state and / or environmental factors and / or the status of an external respiratory assistance device.

[0049] The system may be configured to deliver energy to cause contraction of the respiratory muscles. Additionally or alternatively, the system may be configured to deliver energy to the vagus nerve to reduce inflammation or sepsis and / or to favorably alter the heart rhythm. Further, the system may be configured to stimulate any other nerve or muscle.

[0050] In some embodiments, the transcutaneous lead may include a patch or collar disposed on the surface of the skin. In other embodiments, the system includes a patch or collar configured to be disposed on the skin that includes a microelectrode energy source for the sensor. The lead, patch, or collar may include a chip for product identification, prevention of unauthorized use, and / or retransmission of data to a central data processing location (e.g., where data for more than one patient is processed).

[0051] In some embodiments, the transcutaneous lead may have an antimicrobial coating and / or a reversible anchoring mechanism (e.g., preventing movement of the lead) that can be retained. In some embodiments, the components of the system may communicate via a wireless connection, a Bluetooth® connection, or a sonar connection.

[0052] In some embodiments, the system may include a structure having a plurality of energy sources (e.g., electrodes that dissipate energy), a mechanical ventilator, a control unit connected to the energy sources of the structure, and one or more sensors. The control unit and the one or more sensors may be similar to the control units and sensors described herein. For example, the control unit may be connected to sensors for controlling the synchronization of mechanically ventilated breaths and phrenic nerve stimulation. The system may receive data from sensors (e.g., motion sensors, airway flow sensors, pressure sensors, EMG sensors, central venous pressure sensors, impedance sensors, etc.). The structure may be configured to be placed on the patient such that the energy source is close to the phrenic nerve. For example, the structure may be placed transvascularly, transcutaneously, on the skin, or transesophageally. In some embodiments, energy delivery by the system may be manually triggered by a user action (e.g., a button, voice command, touch screen, etc.). In other embodiments, data received from the sensors can inform the control unit of stimulation parameters (e.g., stimulation timing). Data that inform the control unit of stimulation parameters may include data received from sensors such as motion sensors, airway flow sensors, intratracheal pressure sensors, EMG, EKG, tidal volume sensors, work of breathing sensors, external mechanical work of breathing sensors, O2 level sensors, CO2 level sensors, blood gas sensors, heart rate sensors, and / or stretch receptor signal sensors.

[0053] In some embodiments, the system may map the most efficient and optimal energy source and / or an energy source that causes an undesirable effect based on data received from one or more sensors. The structure may include an antibacterial coating, a chip, RFID, an area that can be better observed by ultrasound, and / or one or more electrodes arranged such that one or more nerves can be stimulated from different directions. In some embodiments, stimulating the nerves from different directions and / or using any of the stimulation train profiles described herein can reduce the fatigue of the associated respiratory muscles. In some embodiments, signals received by the system from a patient module (e.g., a lead, an electrode, a patch) may be wirelessly transmitted via Wi-Fi, Bluetooth, RF, and / or sonar.

[0054] In some exemplary methods, one or more of the foregoing structures may be disposed proximate to the phrenic nerve or the vagus nerve. The structure may be disposed transcutaneously and / or via the neck. Anatomical landmarks and ultrasound imaging can facilitate the placement of the structure. In some embodiments, the placement of the structure may be confirmed based on the patient's response (e.g., response to the delivered energy), data from one or more sensors (e.g., pressure, volume, impedance, nerve activity), palpation, and / or visualization of the diaphragm (e.g., x-ray, fluoroscopy, ultrasound, CT, MRI). Such methods can reconstruct the strength of the diaphragm, prevent atrophy of the diaphragm, maintain the patient's breathing, and / or prevent lung injury to the patient. The method may use any device, system, or structure described herein, including those that include a flexible circuit, an anchor, a delivery cannula, imaging technology, a flexible delivery cannula, a strain relief hole, and / or an electrode.

[0055] Respiratory muscle stimulation may be performed either by directly activating the muscle or by stimulating the associated nerve, such as the phrenic nerve. The stimulation may include the delivery of electrical energy, ultrasonic energy, magnetic energy, chemical energy, or other types of energy well known in the art. The energy source used for the stimulation may be arranged in proximity to the nerve, intravascularly (delivering energy through the vessel wall), percutaneously, on a nerve cuff, through the skin (delivering energy through the skin), or may be directly implanted into the muscle or adjacent tissue.

[0056] Figure 1 shows the anatomical structures of the neck and chest and the relative positions of the left and right phrenic nerves (PhN), vagus nerves (VN), internal jugular veins (IJV), external jugular veins (EJV), brachiocephalic veins (BCV), subclavian veins (SCV), superior vena cava (SVC), and intercostal nerves (IN). The phrenic nerves originate from the cervical spinal nerve roots C3, C4, and C5. The left phrenic nerve extends to the left hemidiaphragm (HD), and the right phrenic nerve extends to the right hemidiaphragm (HD). The left phrenic nerve runs behind the left subclavian vein, enters the thorax through the thoracic inlet, penetrates the lower surface of the diaphragm, and innervates it. The right phrenic nerve passes anterior to the lateral side of the right subclavian artery, proceeds along the superior vena cava and the pericardium of the right atrium of the heart, penetrates the diaphragm at the inferior vena cava opening, and innervates the lower surface of the diaphragm.

[0057] Figure 2 shows a medical system 1000 that includes a percutaneous nerve stimulation lead 1005 and a control unit 1001. The stimulation lead 1005 may include a plurality of energy sources 1006. The energy sources 1006 may be configured to emit, transmit, bypass, and / or deliver energy (e.g., electrical energy, magnetic energy, ultrasound, etc.). The lead 1005 may be placed in proximity to any target nerve or muscle. In some cases, the lead 1005 may be placed in the vicinity of two nerves, such as the left phrenic nerve and the vagus nerve. In some cases, two or more leads 1005 may be placed. Each lead 1005 may be operatively connected to the control unit 1001 (e.g., by a wired connection, wirelessly, etc.). The control unit 1001 may be programmed to perform any of the functions described herein in connection with the system. In some embodiments, the control unit 1001 may be functionally connected to a remote (e.g., handheld, etc.) controller 1002 (e.g., by a wired connection, Wi-Fi, RF, etc.) to enable a patient or a medical professional to remotely control the operation of the control unit 1001 from a distance. The controller 1002 may include a handheld device 1002 as shown in FIG. 2. In some examples, the controller 1002 may include a footswitch / pedal, a voice-activated, a touch-activated or a pressure-activated switch, or any other form of remote actuator. The control unit 1001 may include a touch screen and may be supported by a cart, such as the cart shown in FIG. 8. The system may further include an external respiratory assistance device 1007, such as a mechanical ventilator, for example.

[0058] The controller 1002 (e.g., a remote and / or hand-held controller) may include buttons that can be pushed by a patient or other user to control the breathing pattern. In other examples, the remote controller 1002 may be in the form of a smartphone, tablet, wristwatch, or suitable input device. In one example, the controller 1002 can enable a user (e.g., a patient or healthcare provider) to initiate a sigh breath, thereby allowing a greater volume of air to enter the patient's lungs compared to the previous breath. A sigh breath can occur when the energy source 1006 (e.g., an electrode) of lead 1005 is induced to stimulate one or more of the phrenic nerves at a higher level than normal breathing (e.g., a train of stimuli having a longer stimulus duration or a pulse with a greater amplitude, pulse width, or frequency). A stimulus pulse with a greater amplitude can recruit additional nerve fibers, which in turn can couple to additional muscle fibers and cause a stronger and / or deeper muscle contraction. An extended pulse width or extended duration of the train of stimuli can deliver the stimulus over a longer period of time and extend the duration of the muscle contraction. In the case of respiratory muscle stimulation, a longer duration of a train of stimuli with multiple energy pulses may expand the lower lobes of the lungs by providing a greater or extended negative pressure outside the lungs. Such negative pressure may help prevent or reduce a form of low-pressure lung injury known as atelectasis. For example, an increase in the stimulation of one or more respiratory muscles by phrenic nerve stimulation can result in a more forced contraction of the muscles (e.g., the diaphragm muscle, intercostal muscles, etc.), causing the patient to inhale a greater volume of air and thereby supply the patient with a greater amount of oxygen. A sigh breath can enhance the patient's comfort.

[0059] In other examples, buttons (e.g., on controller 1002 or control unit 1001) may enable a patient or other user to start and stop stimulation therapy, or increase or decrease stimulation parameters including stimulation charge (the product of amplitude and pulse width), the frequency of pulses in a stimulation train, or the respiratory rate. An LED indicator or small LCD screen (not shown) on the controller may provide the operator with guidance or other information regarding stimulation parameters, feedback from system sensors, or the patient's condition. Various target values may be set, and if system information or patient data outside of a predetermined target value is detected, the system may be able to issue an alert or otherwise notify the medical practitioner (e.g., screen notification, text message, alarm, etc.).

[0060] In some embodiments, the control unit 1001 of the system may be implanted in a patient (not shown) along with the stimulation lead 1005. The implantable system may further include a remote controller and a programmer (not shown) that wirelessly communicates with the control unit 1001. In this embodiment, each of the programmer, the control unit 1001, and the remote controller 1002 may include a wireless transceiver so that each component can wirelessly communicate with one another. Each component can be used, for example, to communicate information to a central data storage center or data analysis center (e.g., Wi-Fi, Bluetooth, RF, Z-Wave, etc.).

[0061] The control unit 1001 may include all of the electronics, software, and functional logic necessary to implement the functions described herein. Implanting the control unit 1001 can enable the lead 1005 to function as a permanent respiratory pacemaker. The programmer may enable a patient or medical professional to change or otherwise program nerve stimulation parameters or sensed parameters.

[0062] In some embodiments, the system may include a portable control unit 1001 (see, e.g., FIG. 7). The portable control unit 1001 may include all of the functions of the control unit of FIG. 2, but can be carried by the patient or other user to provide higher portability to the patient. In addition to carrying the control unit 1001, the patient can wear the control unit 1001, for example, on a belt, on other clothing, or around the patient's neck. In other examples, the control unit 1001 may be attached to the patient's bed to minimize the footprint of the system within the area around the patient or to provide portable muscle stimulation when a bedridden patient needs to be transported or moved to another location.

[0063] In a further example, the myoactive lead 1005 is placed within tissue or other blood vessels, advances through the tissue or other blood vessels, and provides access to a position adjacent to a target nerve (e.g., the phrenic nerve) such as the subclavian, superior vena cava, jugular vein (see, e.g., FIGS. 9A and 9B), axillary vein, radial cutaneous vein, pericardial diaphragmatic vein, brachial vein, or radial vein. In addition, the lead 1005 or other stimulation array (e.g., transcutaneous, etc.) may use other forms of stimulation energy such as ultrasound, light, magnetism, etc. to activate the target nerve. In some examples, the system may target other respiratory muscles (e.g., intercostal muscles, abdominal muscles, etc.) in addition to or instead of the diaphragm. The energy may be delivered by one or more methods including transvascular, subcutaneous, nerve cuff, transcutaneous stimulation, or other techniques well known in the art.

[0064] It may be desirable to optimize the method of providing external respiratory assistance 1007 to a patient. In some cases, it may be desirable to ultimately reduce or eliminate the need for the patient to receive external respiratory assistance 1007. The external respiratory assistance 1007 of FIG. 2 may consist of any device or method for assisting in the management of safe blood gas (e.g., CO2, O2, etc.) levels and / or reducing the patient's work of breathing. Some non-limiting examples include mechanical ventilation, non-invasive ventilation (NIV), CPAP, BiPAP, high-flow oxygen / gas, nasal cannula oxygen administration / gas, DPS (Diaphragm Pacing System) (Synapse, Avery, etc.), ECCO2, and ECMO.

[0065] Mechanical ventilation is a term related to positive-pressure ventilation in which mechanical means are used to assist or replace spontaneous breathing. This may involve a machine called a ventilator. Mechanical ventilation is considered "invasive" when it involves any instrument that penetrates the mouth (such as an endotracheal tube) or the skin (such as a tracheostomy tube). There are two main types, namely, positive-pressure ventilation (where air (or another gas mixture) is forced into the trachea by positive pressure) and negative-pressure ventilation (where air is drawn into the lungs (e.g., sucked in) (such as in an iron lung)). There are many modes of mechanical ventilation. Mechanical ventilation may be used when the patient's spontaneous ventilation cannot provide effective gas exchange in the lungs.

[0066] Ventilation can also be provided via a laryngeal mask airway device (e.g., a laryngeal mask). Laryngeal mask airway devices are designed to keep the patient's airway open during anesthesia or loss of consciousness. Laryngeal mask airway devices are often referred to as a type of supraglottic airway device. A laryngeal mask consists of an airway tube connected to an oval mask with a cuff. The cuff is inserted into the patient's mouth, passes down the trachea, and when placed, forms an airtight seal above the glottis (different from the tracheal tube passing through the glottis), providing a secure or stable airway.

[0067] Non-invasive ventilation (NIV) uses airway support administered via a face (e.g., mouth, nose, nose-mouth) mask / cannula instead of an endotracheal tube. The inspiratory gas is often given positive end-expiratory pressure with pressure support or assist-control ventilation where the tidal volume and rate are set. This is called "non-invasive" because the inspiratory gas is delivered by a mask that fits snugly on the face and does not require tracheal intubation.

[0068] Continuous positive airway pressure (CPAP) is a form of positive airway pressure ventilation that continuously applies a weak air pressure to keep the airway of a person who can breathe spontaneously on their own, but may require a certain level of pressure support, continuously open. This is an alternative to positive end-expiratory pressure (PEEP). Both techniques can help to use more of the lung surface area for ventilation to keep the alveoli of the lungs open. PEEP generally refers to a device that applies positive pressure only at the end of exhalation. CPAP devices generally apply continuous positive airway pressure throughout the respiratory cycle, although some systems vary the pressure during the respiratory cycle or over a period of time. Thus, the ventilator itself does not cycle during CPAP and typically does not provide additional pressure above the CPAP level, and the patient must initiate each breath on their own.

[0069] Bilevel positive airway pressure (BiPAP) therapy is very similar in function and design to CPAP. A BiPAP device can also be set to include a respiratory timing feature that measures the amount of breathing a person should do per minute. If the time between breaths exceeds a set limit, the machine can temporarily force the person to breathe and increase the air pressure. The main difference between a BiPAP machine and a CPAP machine is that a BiPAP machine generally has two or more pressure settings, namely a predetermined inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure (EPAP). These two settings allow the patient to move more air in and out of their lungs.

[0070] Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS), is an extracorporeal technique for providing long-term cardiac and respiratory support to patients whose heart and lungs are unable to provide adequate gas exchange. The technology of ECMO is similar to the technology used during cardiopulmonary bypass, which is typically used to provide more short-term support. During ECMO, blood is removed from the person's body, carbon dioxide is removed, and it passes through a device that provides oxygen to the red blood cells. Long-term ECMO patients often experience muscle weakness in the respiratory muscles due to muscle inactivity and other causes.

[0071] Each of these devices / systems and any others known in the art that can be used to manage blood gas levels are collectively referred to as external respiratory assistance 1007. In some embodiments, the stimulation device, array, lead 1005, or components of lead 1005 or parts of the system, such as electrodes, can also monitor the subject's physiological variables by placing them in or on the patient's body. In embodiments where lead 1005 is placed in one or more central veins, the device can monitor physiological variables including, but not limited to, central venous pressure, body temperature, respiratory rate, electrocardiogram, impedance, heart rate, blood flow, CO2, neural activity, EMG, ECG, mixed venous oxygen saturation, and other variables well known in the art. It will be understood that one or more sensors remote from the electrodes, such as one or more of sensors 1020, may be used to monitor such physiological variables.

[0072] In some embodiments, the system may include a respiratory sensor 1009 for detecting parameters of external respiratory assistance 1007 (e.g., a mechanical ventilator). In this regard, the respiratory sensor 1009 may be configured to connect to any standard respiratory circuit used in an intensive care ventilator, and thus the pacing system is independent of the brand of ventilator used. A respiratory sensor 1009, as shown in FIG. 2, can monitor and / or measure some ventilation parameters based on its position within the respiratory circuit and can communicate such parameters to the control unit 1001. As described in more detail below, the respiratory sensor 1009 may be part of a feedback control scheme for adjusting the stimulus applied to the patient or may simply be used as a feedback control scheme for adjusting the stimulus applied to the patient. The ventilation parameters that can be detected may include, but are not limited to, air flow (inspiration and / or expiration), volume, and / or pressure (airway, esophageal, gastric, and / or some combinations / derivatives of the former). In some embodiments, the respiratory sensor 1009 may include or communicate with an accelerometer, gyroscope, and / or motion sensor (e.g., sensor 1020) disposed on the patient's chest cavity. In some embodiments, one or more other sensors may assist in obtaining one or more ventilation parameters. The respiratory sensor 1009 may be connected to the control unit 1001 by wire or wirelessly. In some embodiments, a signal from the external respiratory assistance 1007 may be used to control a respiratory muscle activation part (e.g., a phrenic nerve stimulation part, etc.). Exemplary parameters may be measured both for and from the ventilator. For example, in the embodiment shown in FIG. 2, the respiratory sensor 1009 is external to the external respiratory assistance 1007, and thus the system is of an independent type or model from the external respiratory assistance 1007. However, the system may also be integrated to use internal sensors of the external respiratory assistance 1007, or signals supplied externally by the external respiratory assistance 1007 can provide the system with information for proper operation, and thus the external respiratory sensor 1009 can be omitted.One or more other sensors may detect nerve or muscle activity and may be used to synchronize respiratory muscle energy stimulation with another event. In one example, the sensors of the system detect when the patient is attempting to breathe and deliver positive pressure ventilation and neuromuscular stimulation to the patient. In some embodiments, this delivery of positive pressure ventilation and neuromuscular stimulation can increase the efficiency of the respiratory cycle.

[0073] The stimulation unit (e.g., a controller, control unit 1001, or similar device) may include a signal generator for providing treatment to the diaphragm and other respiratory muscles in response to information received from one or more of the sensors and / or information programmed into the system by a user (e.g., a patient or healthcare provider). In this regard, the stimulation unit may deliver pulses to the stimulation array according to one or more of the protocols described herein. As described in more detail below, in some embodiments, the pulses are generated by a stimulation unit having characteristics suitable for delivering charge to the phrenic nerve to provide sufficient diaphragm recruitment to meet the selected contribution of the diaphragm at the predetermined assist level described above (e.g., in volume, pressure, both, or a parameter derived from volume and pressure).

[0074] The stimulation unit is configured to deliver a fully programmable stimulation towards its end, including, but not limited to, any number of pulses, any combination of defined pulses, any delivery order of defined pulses, multiple instances of any defined pulse, any frequency of stimulation, and / or any delay between pulses (e.g., inter-pulse delay, varying inter-pulse delay, etc.). Each pulse may be independently programmable (e.g., frequency, amplitude, duration, etc.). The stimulation pulses and / or trains may or may not generate a repeating pattern.

[0075] Each pulse may include a charge injection phase and a charge balancing phase (i.e., each pulse may be biphasic). In some embodiments, the duration and amplitude of the balancing phase are programmable as a ratio of the duration and amplitude of the charging phase such that a zero net charge is maintained. The ratio of charge to balance is denoted as the charge:balance ratio (C:B ratio) and is applied such that the product of amplitude and duration (charge) is equal in both the charging and balancing phases. In some embodiments, each pulse is programmable by the following parameters: the ratio of the duration of the charging phase to the duration of the balancing phase, the pulse width range, the stimulation amplitude (current level), and the delay between the charging and balancing phases. The stimulation amplitude may be varied between the same phases (e.g., generating a current that gradually decreases with respect to the charging pulse width). In some embodiments, a zero net charge is preferred. In other embodiments, a non-zero net charge may be used. A volume charge density exceeding 30 μC / (cm phase) has been shown to cause nerve and tissue damage. The systems and methods described herein may include a mechanism to ensure that the volume charge density limit is not exceeded.

[0076] Figure 3 shows exemplary stimulation signals that can be delivered to a target nerve or muscle. For example, with respect to the diaphragm, which is a skeletal muscle, pacing can be achieved by delivering one or more stimulation signals to the phrenic nerve and generating a mechanically effective contraction of the diaphragm. In this regard, the stimulation signal can include a plurality of pulses grouped into stimulation trains. As used herein, a stimulation train is defined as a set of stimulation pulses. This definition does not imply a particular configuration, order of delivery, and / or shape profile or envelope. Figure 3 shows exemplary stimulation trains 1030a, 1030b, 1030c that are generated by a stimulator and delivered to one or more leads 1005 (e.g., energy source 1006, electrodes, etc.) to stimulate the phrenic nerve and include pulses 1031a - 1031h. The stimulation train 1030 may start with two sets (a pair of pulses 1031) or three sets. In some embodiments, two or three pulses 1031 that are quickly consecutive at the beginning of recruitment can increase the entire force profile by shifting the baseline upward at the first onset of recruitment. Similarly, two or three sets delivered midway through the train 1030 can cause a continuous increase in force. An upward shift in early force generation can correspond to generating the same amount of force from the diaphragm over the same period using fewer stimulation pulses 1031. These profiles can be advantageous because excessive activation of muscles such as the diaphragm due to excessive stimulation can induce fatigue. Excessive stimulation of the muscle can also cause a conversion from fast-twitch (strong but easily fatigued) to slow-twitch (fatigue-resistant but unable to produce large amounts of force) muscle fibers.

[0077] Stimulation can be characterized by speed, duration, pulse width, frequency, and signal amplitude. The speed of stimulation can correspond to the number of stimulation trains 1030 delivered per minute. The stimulation speed can correlate with the patient's respiratory rate (e.g., the patient's natural respiratory rate) or the mechanical ventilator speed. The duration of the stimulation train 1030 can mean the length of time during which the stimulation train 1030 is delivered. The pulse width can indicate the duration of each individual pulse 1031 that makes up the stimulation train 1030. Similarly, the frequency can indicate the number of individual pulses 1031 delivered per second. Amplitude can mean the voltage of each pulse 1031 delivered or the average voltage delivered per pulse 1031 of the stimulation train 1030. Without being limited by theory, it is believed that amplitude, frequency, and pulse width can be factors that determine the intensity and other characteristics or parameters of the induced diaphragmatic pacing.

[0078] Figure 4 shows an example of a stimulation train (e.g., a ramp train). In some embodiments, the stimulation train forms a ramp train. For example, a ramp train can be formed by linearly increasing (or decreasing) either the instantaneous frequency of consecutive pulses within the train, the duration (pulse width) of consecutive pulses within the train, or both. A ramp train can indicate that the change in injected charge is induced by programmed stimulation parameters, user activation, or other applied modulations.

[0079] Changes in pulse width and frequency modulation make it possible to design different ramp train envelopes. Referring to FIGS. 4 and 5, during a single pacing ramp, a ramp envelope of only pulse width, only frequency, or both pulse width and frequency can be generated.

[0080] FIG. 5 shows an example in which the pulse width envelope and the stimulation frequency envelope can be modulated together or individually to generate a desired ramp sequence during pacing. For example, referring further to FIG. 5, the combined AF (far left) can cause a stepwise recruitment of the diaphragm motoneurons at a constant frequency (no firing rate), and the combined BA (second from left) can gradually recruit and derecruit the motoneurons with a steadily increasing firing rate, but any combination is possible. Irrespective of the firing rate, it is also possible to change the speed (gradient) of recruitment and derecruitment of the motoneurons by adjusting the relative proportions of the durations of the increase and decrease of the pulse width within a single pacing ramp. Further, the present disclosure considers the mathematically defined pulse width and frequency modulation as separate piecewise functions in time, thereby enabling the generation of any desired ramp envelope.

[0081] Multiple sets of ramp sequences can be generated, and there are some embodiments in which the ramp sequences are configured to implement one or more of the following. 1) Mimicking the physiological contraction of the diaphragm by separately controlling recruitment and firing rate using pulse width and frequency modulation, respectively, 2) Delaying the onset of neuromuscular fatigue, 3) Promoting the movement of fluid or other substances from or within the airway, 4) Maintaining or restoring the natural fiber composition of a healthy diaphragm, and / or 5) Conditioning the diaphragm to promote the growth of specific fiber types (e.g., type I, slow-twitch muscle fibers, fatigue-resistant fibers, etc.). Other exemplary stimulation profiles are described herein (e.g., those of FIG. 19) and may be used in combination with a portion of the stimulation profiles described in FIGS. 3 - 5.

[0082] FIG. 6 shows some anatomical landmarks near the phrenic nerve. The phrenic nerve originates from the cervical spinal nerve roots C3, C4, and C5. The spinal nerve root C4 contributes mainly, with less contribution from C3 and C5, and some communicating with the fibers of the cervical plexus. This nerve originates at the lateral border of the anterior scalene muscle. The nerve then passes inferiorly over the anterior surface of the anterior scalene muscle and deeply to reach the prevertebral leaf of the cervical fascia. On both sides, the nerve runs posterior to the subclavian vein.

[0083] Referring further to FIG. 6, in one or more embodiments, the phrenic nerve stimulation device may stimulate the left PhN. Some energy sources 1006 that may also function as sensors may be distributed in an array configuration along the lead 1005. The energy emission may be focused in one axial direction from the array, or may spread radially uniformly in multiple directions. The nerve stimulation device may be fixed to the patient to reduce or mitigate the degree of movement of the stimulation array over time. Suitable fixation or anchoring mechanisms 1015 may include adhesive patches or sutures. The fixation or anchoring mechanism 1015 may also assist in the orientation of the lead 1005 such that the energy source is focused towards the target nerve or muscle.

[0084] FIG. 7 shows a medical system 1000 including two percutaneous leads 1005 each having a plurality of energy sources 1006. One lead 1005 is disposed near the left phrenic nerve and the other lead 1005 is disposed near the right phrenic nerve. The percutaneous leads 1005 may also be arranged to stimulate the vagus nerve, the phrenic nerve and both the vagus nerve, or other nerves as desired. The energy source 1006 is electrically connected to a can 1025 that may house logic circuitry, a battery or other energy storage element and / or other electronics. The can 1025 may be implanted in the patient. The electronics and energy storage elements may also be embedded in a skin patch that can be attached to the patient's skin. The patch and / or can 1025 may interact with a programming unit, a control system, a control unit 1001, or other systems via a wired or wireless connection.

[0085] FIG. 8 shows a medical system 1100 including a neck collar 1105 having a plurality of energy sources 1106. The collar can be connected, either wired or wirelessly, to a control unit 1101. The neck stimulation device (neck collar 1105) can activate the nearby phrenic nerve, vagus nerve, or other nerves. The control unit 1101 may include a computer on a cart (e.g., including a touch screen or other graphical user interface). The control unit 1101 may communicate (e.g., wirelessly) with the various components of the system. Similar to other systems described herein, the system 1100 may optionally include external respiratory assistance 1107 and / or a respiratory sensor 1109 or other sensors.

[0086] Sensors 1120 on the patient's left and right torso can transmit physiological information to the control unit 1101. In some embodiments, a motion sensor on the diaphragm can provide information regarding diaphragm contraction / motion. Similar sensors may be used to detect the contraction or motion of other muscles (e.g., intercostal muscles). In some embodiments, the sensors 1120 can deliver energy and cause the activation of one or more respiratory muscles. In some embodiments, impedance sensors may assist in detecting the distribution of gas within various lung regions of the patient and / or sensing the state of tissues within the body, as described below.

[0087] EIT may be used to monitor lung function. The impedance of lung tissue can be approximately five times greater than that of most other soft tissues in the torso region. The difference in impedance results in a high contrast of the lungs. In addition, the resistivity of the lungs can increase and decrease several-fold during respiration (e.g., between inhalation and exhalation). The impedance measurements can help characterize and distinguish between lung conditions resulting from regions of lower resistivity (e.g., hemothorax, pleural effusion, atelectasis, pulmonary edema, etc.) and regions of higher resistivity (e.g., pneumothorax, emphysema, etc.).

[0088] The electrical impedance of lung tissue can change over time depending on the air volume. For example, the electrical impedance of the chest wall changes during inhalation and exhalation. The chest wall exhibits an electrical impedance that includes two components, namely, a relatively constant value and a changing value. The change in impedance can result from one or both of the following two effects during inhalation. 1) An increase in gas volume relative to the fluid volume in the chest, which can cause a decrease in conductivity, and 2) an increase in the length of the conductive path (e.g., between two electrodes) when the lungs expand. These effects can cause an increase in impedance during inhalation. There is an approximately linear correlation between the impedance change during the respiratory cycle and the volume of air. The changing component of impedance (e.g., respiratory impedance) generates a voltage component that changes when a current is injected (e.g., by electrodes). This changing voltage component can be used to determine the respiratory rate of the subject.

[0089] Impedance information can be used to characterize, for example, the dynamic respiratory state of a patient, such as the air distribution within various lung regions. The air distribution within various lung regions can be used to determine the need to maintain or adjust parameters of the devices or systems described herein, such as, for example, stimulation energy, stimulation pulse amplitude, stimulation pulse width, stimulation pulse frequency, stimulation duration, stimulation rate, and / or the interval between stimulations / pulse trains (e.g., respiratory muscle activator (RMA) parameters).

[0090] One or more embodiments are designed to utilize real-time monitoring of EIT to measure changes in the distribution of lung volume between the left and right, and anterior and posterior lung regions. Further methods and systems described herein compare the lung gas distribution to a more optimal target distribution in order to maintain or improve the ideal air distribution, evaluate the need to adjust the air distribution towards a more optimal gas distribution, and can determine and / or deliver an appropriate stimulation energy profile of the respiratory muscle activity (RMA) to achieve the desired lung gas distribution during the respiratory phase. In some embodiments, the system may include external respiratory support (ERS) (e.g., CPAP, mechanical ventilator, high-flow oxygen, ECMO, ECCO, etc.), and the settings of the ERS and RMA can be adjusted to ensure proper gas exchange and reduce the likelihood of patient injury (e.g., VILI, barotrauma, low tidal volume, high tidal volume, etc.). To assist in determining appropriate ERS and RMA settings, one or more sensors (e.g., heart rate sensor, CO2 sensor, O2 sensor, respiratory sensor, temperature sensor, motion sensor, electromyogram recording sensor, electrocardiogram recording sensor, airflow sensor, pressure sensor, etc.) may also be used.

[0091] As described above, impedance information can be used to characterize a patient's respiratory state, such as the air distribution within various lung regions, thereby determining the need to maintain or adjust respiratory muscle activity (RMA) parameters (e.g., energy, stimulation pulse amplitude, stimulation pulse width, stimulation pulse frequency, stimulation duration, interval between stimulations / pulse trains (e.g., stimulated respiratory rate), etc.).

[0092] As described above, the lung gas distribution device described herein may include a belt containing impedance sensing electrodes. When the impedance sensing electrodes are placed at various locations on the patient's torso, they can determine the distribution of gas within various regions of the patient's lungs.

[0093] Tissue impedance sensing (TIS) is a type of tissue property diagnosis in which the conductivity, permittivity, and / or impedance of a body part are inferred from electrode measurements and can be used to form tomographic images or multi-dimensional analyses of tissue state or composition. Conductivity varies significantly between various biological tissues and in response to the movement of fluids and gases within tissues. A TIS system can apply a small alternating current of a single frequency, or alternatively, the TIS system can use multiple frequencies to better distinguish between tissue types.

[0094] Figures 9A and 9B show an exemplary system 1200 that includes a respiratory muscle stimulation lead 1205, an external respiratory assistance device 1207, a respiratory sensor 1209, a pulmonary gas distribution sensor (e.g., one or more electrodes or other energy sources 1206, e.g., internal sensors, external sensors, electrode arrays 1225, etc.), and a control unit 1201. The control unit 1201 may be configured to adjust the parameters of the stimulation and external respiratory assistance device 1207 to improve / maintain an optimal gas balance within various regions of the patient's lungs during one or more respiratory cycles.

[0095] In some embodiments, the respiratory muscle stimulation lead 1205 may include a lead body or cannula that passes through the patient's skin and into a blood vessel. The cannula may include one or more energy sources 1206 and / or sensors (e.g., electrodes). As shown in FIGS. 9A and 9B, at least one energy source 1206 may be disposed either on or under the patient's skin. Further, one or more energy sources 1206 may be arranged to stimulate the left vagus nerve, one or more energy sources 1206 may be disposed within a blood vessel, one or more energy sources 1206 may be arranged to stimulate the left phrenic nerve, one or more energy sources 1206 may be disposed within a blood vessel to stimulate a nerve transvenously, and / or one or more energy sources 1206 may be arranged to stimulate the right phrenic nerve. The energy source 1206 may be located on the skin, within tissue, within a blood vessel, or at any other location suitable for nerve and / or muscle activation.

[0096] In some embodiments, the conductive surface electrodes 1226 and / or one or more other sensors (e.g., impedance sensors) may be attached to the skin around the patient's torso. Alternatively or in addition, internal electrodes may be used to evaluate impedance. Referring to FIGS. 9A and 9B, the electrodes 1226 on the belt 1225, the electrodes 1206 on the cannula / needle / catheter, or both may be used to evaluate the impedance of tissue and / or to stimulate the respiratory muscles.

[0097] Referring to FIG. 9B, one or more electrodes 1226 may be attached substantially at the height of the sixth rib, perpendicular to the axillary line, on any of the patient's front, back, side, or any combination thereof. If desired, one or more electrodes 1226 may be placed at reference positions such as directly under the collarbone or the sternal angle, below the rib cage, and / or at the height of the xiphoid process at the axillary line. In other configurations, the electrodes 1226 may be placed higher or lower on the patient to facilitate impedance detection and / or muscle stimulation. In some embodiments, one or more electrodes 1226 may be placed in other positions and configurations depending on the patient and other physiological conditions (e.g., the presence of implants such as a heart pacemaker, etc.).

[0098] One or more impedance electrodes 1226 may be disposed on one or more leads 1205 that can be easily attached to and removed from the patient. For example, two or more electrodes 1226 may be arranged in a linear array, a grid pattern, and / or a configuration designed to conform to the patient's anatomical structure. In some embodiments, four or more electrodes 1226 are arranged in a linear array and / or a grid array.

[0099] In some embodiments, the plurality of electrodes 1226 are arranged as a belt 1225, a vest, and / or an array. Preferably, one or more electrodes 1226, electrode leads, and / or sensors may be placed around the patient's torso, on the subject's rib cage or abdomen. The systems and methods described herein may use single-use electrodes or multi-use electrodes. The impedance array may be configured with attachment means (e.g., tape, glue, elastic straps, adjustable belt 1225, or other fastening members, etc.) for securing the electrodes or the array to the patient. The array may also incorporate a soft cloth, foam, non-silicone material, etc. to reduce the likelihood of skin inflammation.

[0100] Electrodes and configurations of different sizes can be used for patients of different sizes (e.g., adults, children, newborns, high BMI, low BMI, etc.). In some embodiments, the electrodes may have a surface area of about 2 mm 2 ~ about 6 mm 2 .

[0101] In some embodiments, the impedance electrodes may be enabled for both delivering electrical impulses to the body and detecting impedance. In other embodiments, some of the electrodes may only deliver electrical impulses, and some electrodes may only detect impedance. In some embodiments, the impedance electrodes may be used to detect a patient's physiological information such as neural activity, ECG, body temperature, or movement as described herein. When used for detection, one or more of the electrodes may be electronically coupled to a signal acquisition module. The signal acquisition module can receive signals from the electrodes.

[0102] The electrodes and / or other sensors described herein may be electrically connected to a remote control unit 1201 (e.g., via a wired or wireless connection) and may be configured to transmit data to a remote sensor or a control center / device / system / controller. The electrodes and sensors may include a local power source such as a button cell battery. The electrodes and sensors may be electrically connected to an external or remote power source.

[0103] One or more impedance sensors may be configured to collect data over time. Signals can be recorded over several breaths (e.g., over a fixed time interval such as 15 seconds, 30 seconds, or other durations). Detection may be performed continuously or intermittently. Detection may be performed at predetermined and variably selected intervals (e.g., over at least 5, 10, 20, or up to 50 patient breaths, over at least 200 patient breaths, over at least 2000 patient breaths, or over another duration).

[0104] As described above, the impedance electrode may be disposed within the patient's body. As an example, the electrode may be located on the percutaneous lead body. As another example, the electrode may be disposed on a transvascular device such as a catheter described in this specification and patents and publications incorporated herein by reference. The impedance may be measured between any two electrodes of the lead body (e.g., catheter), between a catheter electrode and a skin electrode, or both. In some embodiments, the impedance may be measured between a) either the most proximal electrode or the hub, and b) a distal electrode on the catheter.

[0105] The impedance exhibited with respect to the injected current (e.g., current transmitted from one or more electrodes) may depend on the conductivity of the fluid surrounding the electrode or adjacent to the tissue within the local region between a pair of sensing electrodes. The conductivity may also depend on the cross-sectional area of the blood vessel at the location of the electrode. The impedance of the electrode may vary depending on the medium on which the electrode is placed. For example, an electrode disposed in a relatively large amount of conductive fluid may have a lower impedance than an electrode placed on the blood vessel wall.

[0106] Signal filtering, processing, and analysis techniques described herein and well known in the art may be used to evaluate the impedance measurements in real time. Changes in the impedance profile, other physiological information, and / or warnings or notifications may be displayed to a medical professional, subject, or other user on a graphical user interface.

[0107] Various sensors may be used to correlate the stimulation with the patient's respiration, to correlate the stimulation with the delivery of respiration from a mechanical ventilator, or both. The sensors may detect heart rate, CO2, O2, respiration, body temperature, movement, impedance, electromyogram, electrocardiogram, airflow, pressure, or any combination thereof.

[0108] The respiratory therapy system 1200 described herein (e.g., as shown in FIGS. 9A and 9B) may be used to manage the flow of gas to and / or from a patient's lungs. The system may include a control unit 1201 for managing the performance of the respiratory therapy system. The system may further include at least one energy emitter 1206 (e.g., a stimulation array, an electrode lead, a stimulation catheter, etc.) for delivering energy to cause contraction of the respiratory muscles, and the energy emitter is functionally connected to the control unit 1201 (e.g., by wire or wirelessly, etc.). As an example, the stimulation array may be disposed either inside or outside the patient, and / or may incorporate a combination of both internal and external components. The stimulation array may include a catheter, a cannula, a needle, a lead body, a transcutaneous emitter (e.g., TENS, etc.) or other devices described herein or well-known in the art.

[0109] The system may include one or more impedance sensors 1226 for acquiring bioelectrical impedance signals from the patient, and the impedance sensors 1226 are functionally connected to the control unit 1201. As described herein, the impedance sensors 1226 may be located either inside the subject, outside the subject, or both.

[0110] The controller or control unit 1201 receives the bioelectrical impedance signal, analyzes the bioelectrical impedance signal, determines an approximate air distribution between lung regions (e.g., posterior, anterior, left, right, upper, lower, etc.) for a desired air distribution within lung regions (e.g., each left and right posterior and anterior regions), and further adjusts the stimulation parameters so that the energy delivered by the stimulation array can change the air distribution in the lungs.

[0111] The stimulation array may include an array configured to stimulate the respiratory muscles on the right side of the patient and an array configured to stimulate the respiratory muscles on the left side of the patient. The stimulation levels can be adjusted separately to balance the volume of air in different regions of the patient's lungs. For example, increasing the stimulation energy targeted at the right diaphragm muscle may assist in shifting the air or gas distribution from the upper lung regions to the lower lung regions. This can enable ventilation of patients with lower pressures in the upper / anterior lung lobes at the same tidal volume, thereby reducing atelectasis in the lower / posterior right lung and / or reducing the likelihood of barotrauma in the upper right lung. In some embodiments, the reduction in upper lung pressure can reduce signal transmission from the pulmonary stretch receptors, thereby also reducing VIBI.

[0112] The system described herein may operate in an autonomous mode, i.e., mode A. Mode A is a life support mode that can operate independently of external respiratory assistance. In some embodiments, such as those shown in FIGS. 2 and 7-9B, routines for implementing one or more functions including the autonomous mode may be executed by the system. In this regard, mode A operates in a closed-loop control manner using feedback from various sensors, such as one or more of the sensors (e.g., sensor 1020 and / or impedance electrode 1226). These sensors may be used to monitor physiological variables, which can include but are not limited to central venous pressure, mixed venous oxygen saturation, heart rate, and level of motor activity. Mode A may provide adjustable diaphragmatic pacing for patients who have no, some, or full native spontaneous breathing ability and require respiratory assistance. The system may automatically adjust as needed to the patient's physiological needs and changing activity levels.

[0113] In some embodiments, a system operating in mode A may be connected to a backup external respiratory assistance 1007. For example, mode A may be applicable to patients who are permanently dependent on a mechanical ventilator or otherwise require continuous pacing by the system.

[0114] In some embodiments, in contrast to some systems for implementing a Pacer-Initiated Ventilation Mode and a Ventilator-Initiated Pacing Mode, the system for implementing Mode A may be fully implanted under the patient's skin in the upper chest region. As described above, the system may be powered by a power storage source such as a primary or rechargeable implantable battery and may be integrated with other implantable devices that support the patient's heart or other functions. Continuous data collection may be used to create near real-time images / videos of the desired tissue and monitor lung function.

[0115] A small alternating current may be applied through some or all of the electrodes, and the resulting potential may be recorded by one or more other electrodes. The free ion content of the tissue or body fluid determines the conductivity of the tissue or fluid. For example, muscle and blood conduct the applied current with a lower impedance than, for example, fat, bone, or lung tissue. Changes in impedance may be used, for example, to reconstruct the characteristics of the target tissue, such as by creating a static image. This process may be repeated in many different electrode configurations to generate learned tissue characteristics. As an example, data for characterization may be used to construct a multi-dimensional tomogram by an image reconstruction algorithm (known as electrical impedance tomography / scanning, i.e., EIT / EIS).

[0116] In one embodiment, the impedance electrodes may be configured to also serve as a stimulator and may be used to stimulate the intercostal muscles to assist exhalation and may be used, for example, in combination with an inspiratory stimulator array (e.g., phrenic nerve needle or catheter stimulation), to manage a portion of both the patient's inhalation and exhalation.

[0117] The system of this specification may further include an external respiratory assistance device such as a positive pressure breathing device for delivering gas to a patient's lungs. In such an embodiment, the respiratory therapy system may detect the operation of the positive pressure breathing device by a sensor or may be functionally connected to the positive pressure breathing device. The controller can optimize the delivery of positive pressure from the positive pressure breathing device and / or stimulation energy from the respiratory muscle stimulator to balance the gas levels and flows within various regions of the patient's lungs during the respiratory cycle.

[0118] Figures 10A - 10H show exemplary delivery devices, sheaths, cannulas, needles, flexible stimulation lead structures, energy sources, and anchoring mechanisms. Other cannula / needle / catheter designs such as those described in U.S. patents and publications incorporated by reference may be implemented. In the example, as shown in Figures 10A - 10D, the lead 1005 may initially be incorporated within a needle (e.g., including stainless steel, polymer, etc.) or an introducer sheath. The delivery device for positioning the stimulation array (e.g., an array including the energy source 1006) may include a long cannula / needle / catheter 1050.

[0119] The cannula / needle / catheter 1050 may have a relatively smooth outer surface, a small cross - sectional area, and a tip - side tip suitable for passing through the skin and tissue as compared to conventional cannulas. One or more embodiments including the cannula / needle / catheter 1050 may include a channel or lumen defined by the body of the cannula / needle / catheter 1050 suitable for receiving a guidewire, a stylet, and / or the stimulation lead 1005.

[0120] The cannula / needle / catheter 1050 may be conductive and may be arranged to enable local nerve stimulation. The cannula / needle / catheter 1050 may be rigid, flexible, or controllably flexible to assist in steering the stimulation lead 1005 to the desired site. As shown in FIGS. 10A and 10B, the cannula / needle / catheter 1050 may have an energy emitter 1056 (e.g., located at the tip-side tip) configured to assist in the placement of the stimulation array. In this example, the cannula / needle / catheter 1050 may be connected to the stimulation unit and / or the control unit to directly provide signals to the energy emitter 1056 at the tip-side tip, or may be connected to other parts of the cannula / needle / catheter 1050 (e.g., to assist in the manipulation of the tip-side tip towards the desired position). In some embodiments, the energy emitter 1056 may be attached to the outer surface of the cannula / needle / catheter 1050 such that at least one electrode (e.g., the energy source 1006) can be advanced in the vicinity of the target nerve (e.g., the phrenic nerve, the vagus nerve, etc.) for stimulation. A second electrode (not shown) may be connected to the patient's skin to create a return path for the electrical stimulation.

[0121] The cannula / needle / catheter 1050 or lead 1005 may include a stylet or obturator that can be inserted through a passage to provide the desired level of rigidity to the cannula / needle / catheter 1050 or lead 1005. When removed, this passage or another passage may be used for fluid / drug delivery or other purposes. Various shaped stylets may be used to improve the steerability during positioning of the cannula / needle / catheter 1050 or lead 1005 (e.g., a bent tip and / or an angled tip). When the stylet is removed, the lumen may be used to insert the stimulation array into the patient.

[0122] In some embodiments, the elongated cannula / needle / catheter 1050 is linear, non-linear, flexible, suitable for steering towards the target nerve, or a combination thereof. The cannula / needle / catheter 1050 may include visualization means such as ultrasonic capabilities to enable optimal positioning of the stimulating electrodes, such as the energy source 1006. In some cases, the cannula / needle / catheter 1050 is used to deliver the electrode array to the desired location, after which the cannula / needle / catheter 1050 may be removed from the body. For example, a split or peel-away cannula may be used.

[0123] In some embodiments, the stimulation array (e.g., an array including one or more leads 1005 and / or energy source 1006) may be suitable for steering towards a target nerve (e.g., flexible). The lead 1005 and / or energy source 1006 for stimulation may be folded, rounded, twisted, wound, and / or wrapped so as to easily fit within a lumen or channel within the elongate cannula / needle / catheter 1050. Thereafter, the lead 1005 and / or energy source 1006 can be advanced and placed at a desired location, at which point the energy source 1006 and / or lead 1005 can return to another geometric configuration. In some embodiments, the array may include a plurality of electrodes (e.g., energy source 1006) disposed around the shaft. For example, a flexible circuit may be wound such that the discrete energy source 1006 directs its energy in a specific direction radially out of the cannula / needle / catheter 1050 into the excitation region. The cannula / needle / catheter 1050 may include an extruded polymer tube (e.g., catheter) or a metal needle. The flexible cannula / needle / catheter 1050 may include a direction indicator on the outside of the cannula / needle / catheter 1050 to provide the clinician with an indication of direction. The cannula / needle / catheter 1050 can be oriented (longitudinally, axially, etc.) to achieve a desired position for optimal stimulation. The fixation means described herein assist in locking the stimulation array in place. The fixation device may include an adjustment mechanism for making fine adjustments to the position of the stimulation array that provides a slight, and in some cases progressive, forward or backward movement of the array.

[0124] In one or more embodiments, the stimulation array may be delivered through a delivery cannula / needle / catheter 1050 that may include needles or other guiding tools for placing the array. The delivery cannula / needle / catheter 1050 and / or the stimulation array may contain markers (e.g., radiopaque markers) that are visible via ultrasound, x-ray, or other means to assist with placement. After placement of the array, other external markers may be placed on the patient's skin, e.g., by a temporary dressing, to provide a future reference for the location of the stimulation array.

[0125] Identification and / or positioning of the phrenic nerve may be performed using anatomical landmarks, ultrasound, and / or 3D images generated by CT scans or MRIs. Insertion of the cannula / needle / catheter 1050, energy source 1006, and / or lead 1005 may be at a height approximately at the level of the C5 vertebra, outside the margins of the cricoid cartilage and the sternocleidomastoid muscle (SCM). The patient may first be evaluated to determine suitability for insertion of the stimulation lead 1005. Using ultrasound or other imaging techniques, it can be determined whether the patient's anatomical structure is suitable for insertion of the stimulation electrodes and / or lead 1005. Anatomical landmarks (such as bones / veins (using ultrasound) external landmarks, etc.) may be evaluated and used to place the lead 1005. Once the insertion site is determined, the area around the insertion site may be cleaned and sterilized.

[0126] Typically, the subject's skin can be prepared and / or cleaned for placement of the sterilized device. A sterile drape may be applied. A local anesthetic may be administered. In some cases, the skin can be incised or opened with a scalpel or blade to facilitate insertion of the stimulation array and / or delivery system (e.g., a system including cannula / needle / catheter 1050). Fluoroscopy, ultrasound, or other navigation means may be used to guide placement of the cannula / needle / catheter 1050 and / or the stimulation array. A surgical dressing may be placed over the insertion site. Antibiotics or other means may be used to reduce the risk of infection at the skin access site.

[0127] In one embodiment, the cannula / needle / catheter 1050 is inserted through the skin typically at an angle of 45 degrees or less, and when the stimulation array is positioned, the tip of the cannula / needle / catheter 1050 is in the vicinity of the target nerve (e.g., phrenic nerve, vagus nerve, etc.), more preferably advanced past the target nerve, so that at least one or more energy sources 1006 (e.g., electrodes) on the array can be close to the target nerve. Then, it advances under the sternocleidomastoid muscle (SCM) parallel to the muscle fibers of the anterior scalene muscle (ASM). Thereafter, stimulation energy can be delivered to the tissue adjacent to the delivery device (e.g., cannula / needle / catheter 1050) during placement of the delivery device to assist in positioning the cannula / needle / catheter 1050 at a desired position relative to the stimulation target (e.g., diaphragm, phrenic nerve, vagus nerve, etc.).

[0128] In one embodiment, such as that shown in FIGS. 10A and 10B, the cannula / needle / catheter 1050 can include a separate stimulation array of one or more energy sources (e.g., tip-side tip energy emitter 1056). When the cannula / needle / catheter 1050 is placed and the diaphragm or other target nerve or muscle responds to the stimulation, multiple electrode leads can be advanced within the cannula / needle / catheter 1050 (e.g., as shown in FIGS. 10C - 10D).

[0129] In some embodiments, the cannula / needle / catheter 1050 may include a window, aperture, and / or hole 1055 that aligns with the energy source 1006 of the stimulation array (as shown in FIGS. 10B - 10D). The cannula / needle / catheter 1050 and / or the stimulation array may have alignment features (such as markings, mating connectors, etc.) such that when the stimulation array is properly positioned within the cannula / needle / catheter 1050, at least a portion of one or more electrodes is visible through one or more holes 1055. When advancing the cannula / needle / catheter 1050 into the tissue, a specific energy source 1006 (such as an electrode) on the stimulation array can be activated to penetrate the surrounding tissue with an electric field. The response of the respiratory muscles to the stimulation (such as a single twitch or contraction of the diaphragm) can be manually detected and visualized on an external monitor such as a respiratory monitor and / or measured by different types of sensors described herein.

[0130] As shown in FIGS. 10C - 10I, the distal tip of the stimulation lead 1005 may have an expandable feature for anchoring the lead 1005 in a predetermined position. Anchoring features may include barbs, expandable portions, shape-changing portions, expandable nitinol components, tines, inflatable balloons, shape deformations, mechanical systems of flexible tines, mechanical systems where tines are left in place upon removal of a stylet, and / or other anchoring features well-known in the art or described herein. For example, other anchoring features such as sutures, adhesives, dressings, and other devices well-known in the art may be applied external to the patient. Embodiments including anchoring features are shown, for example, in FIGS. 10C - 10H.

[0131] In some embodiments, when the cannula / needle / catheter 1050 is in the desired position, the cannula / needle / catheter 1050 may be retracted slightly to expose one or more anchoring features on the stimulation lead 1005. The stimulation lead 1005 may then be anchored in place. In other embodiments, the anchor feature may be actuated to extend beyond the cannula / needle / catheter 1050 to secure the stimulation lead 1005, and then the cannula / needle / catheter 1050 may be retracted.

[0132] The position of the multi-electrode lead 1005 can be confirmed (e.g., by ultrasound, etc.). When the lead 1005 is in the appropriate position, as shown in FIGS. 10D and 10E, the cannula / needle / catheter 1050 can be carefully removed from the patient. The cannula / needle / catheter 1050 may be split or grooved. In some cases, the cannula / needle / catheter 1050 may accommodate snap wings that are bent or manipulated to split or create a longitudinal channel within the cannula / needle / catheter 1050. Thus, the cannula / needle / catheter 1050 may be split open to create a path and removed from the lead 1005 or stimulation array by the path. In other embodiments, the cannula / needle / catheter 1050 can be removed on the tip of the stimulation lead 1005.

[0133] Referring to FIGS. 10C-10E, in some embodiments, the stimulation lead 1005 may include a plurality of expandable legs. The legs may be biased to expand while disposed within the lumen of the delivery device and extend outwardly when the legs advance sufficiently beyond the tip of the cannula / needle / catheter 1050. Any suitable number of expandable legs may be present, and the legs may be made of any biocompatible material such as, for example, plastic and / or shape memory metal alloy. The tips of the legs may be configured to attach to tissue such as, for example, tissue proximate to one or more stimulation targets.

[0134] FIG. 11 shows a lead 1005 having expandable arms that form a basket. Each arm may have a plurality of energy sources 1006. In some embodiments, the basket may be in a folded state while being disposed within a cannula / needle / catheter 1050, and may be biased to expand and transition to an expanded state as the basket advances beyond the distal tip of the cannula / needle / catheter 1050. The lead 1005 may be designed to be easily removable by inserting a sheath that can fold the anchoring mechanism over the lead 1005. Each expandable arm may include an insulated electrical conductor connected to the lead 1005 and one or more electrodes (e.g., energy sources 1006). In some embodiments, the lead 1005 may be inserted into an anatomical lumen (e.g., a blood vessel), and the basket may expand to allow the plurality of electrodes to contact the wall of the lumen at various radial positions.

[0135] Referring to FIG. 12, the flexible circuit 1070 may include electrical traces, chips, sensors, energy sources 1006, and / or other electrodes wrapped around or attached to a polymer or metal tube / cannula 1050 and / or one or more other lead body structures. The components of the flexible circuit 1070 may be coupled or fixed in place. This type of structure can provide a very flexible lead 1005 that can be manufactured at low cost and easily.

[0136] The control system can periodically deliver stimuli by various combinations of energy emitters (e.g., electrodes, transducers, etc.), and can optimize the selection of the ideal emitter (e.g., leads or electrodes) using external feedback such as sensors. In some embodiments, an impedance sensor may detect the volume of air within various lung regions, and the system can adjust the stimulation profile to achieve the desired lung air distribution. In one or more embodiments, an airflow sensor may measure the flow of air from an external respiratory assistance system to the patient, and the control unit may adjust the stimulation profile to manage the amount of air moved by the patient's respiratory muscles and the amount of air moved by external respiratory assistance.

[0137] For example, when one or more stimulation arrays are placed at two different locations to stimulate, for example, the left and right phrenic nerves or, as another example, the left and right intercostal muscles, the leads extending from or attached to two or more locations can be fixed together, providing a cleaner bundle of leads / wires that connect to an external control unit / stimulator.

[0138] FIG. 13 shows an embodiment of subcutaneous stimulation using electrode microneedles 1303 housed within an array. The microneedle 1303 array has connection means (e.g., wireless, wired, etc.) to a stimulation control unit. The microneedle 1303 array may house another energy source such as an ultrasonic wave for phrenic nerve excitation by another polar electrode array (monopolar, bipolar, tripolar, or multipolar) that generates an electric field or a single or multiple microneedle 1303 arrays.

[0139] The tip of the micro-needle array can be inserted into the subcutaneous layer on the proximal side of the position of the target phrenic nerve or any other target nerve (e.g., the left side of the neck or the right side of the neck). Inserting a bipolar micro-needle array into the subcutaneous layer on the left side of the neck may enable the excitation of the left phrenic nerve. Inserting a bipolar micro-needle array into the subcutaneous layer on the right side of the neck may enable the excitation of the right phrenic nerve. Phrenic nerve excitation can result in the recruitment of the left hemidiaphragm, the recruitment of the right hemidiaphragm, or the recruitment of the entire diaphragm.

[0140] The micro-needle array may be attached to a patch configured to be placed on the surface of the skin. The patch may house an energy source (e.g., a battery, etc.), electronic devices, logic, circuits, communication means, sensors, memory, and / or chips.

[0141] Referring to FIG. 14, for percutaneous access, electrodes 1406 embedded in the adhesive contained within the adhesive patch array may be used. The adhesive patch array may have connection means (wired or wireless) to a stimulation control unit. The adhesive patch array may house one or two or a plurality of electrode arrays 1406 (monopolar, bipolar, tripolar, or multipolar) that generate an electric field for phrenic nerve excitation from one or more adhesive patch arrays.

[0142] The distal portion of the adhesive patch may be attached to the epidermis on the proximal side of the position of the target phrenic nerve (e.g., the left side of the neck or the right side of the neck). Fixing the adhesive patch array to the epidermal layer on the left side of the neck may enable the excitation of the left phrenic nerve. Fixing the adhesive patch array to the epidermal layer on the right side of the neck may enable the excitation of the right phrenic nerve. The patch may house an energy storage element (battery), electronic devices, logic, circuits, communication devices, sensors, memory, and / or chips.

[0143] In some embodiments, the energy emitter / source (e.g., lead or electrode) extends 270° or less around the outside of the stimulation lead and / or cannula / needle / catheter. The energy emitter / source (e.g., lead or electrode) may extend anywhere within the range of 1° to 270° around the outside of the stimulation lead and / or cannula / needle / catheter. In one or more embodiments, the energy emitter / source (e.g., lead or electrode) may extend up to 360° around the surface of the stimulation lead and / or cannula / needle / catheter. This configuration may enable the electrode to have a more focused or local stimulation.

[0144] The electrode may extend 180° or less around the outside of the lead, for example, in a range such as 30° to 120°, or 60° to 90°, around the outside of the lead. For example, it may be desirable to stimulate another nerve or anatomical structure (e.g., phrenic nerve, etc.) while avoiding stimulating a particular nerve or anatomical structure (e.g., brachial plexus). In other embodiments, for example, while stimulating one nerve such as the phrenic nerve with one set of stimulation parameters to provide natural diaphragmatic respiratory contractions, it may be desirable to use an emitter in a different direction to stimulate a second nerve such as the vagus nerve to provide anti-inflammatory signaling to the brain and / or to treat sepsis.

[0145] Furthermore, if the flexible lead / cannula / sheath includes a directional emitter, e.g., an electrode, the electrode may generate an electric field whose energy intensity varies according to the circumferential angular position relative to the longitudinal axis of the flexible lead at a given longitudinal position along the lead and the axial distance from the surface of the stimulating electrode.

[0146] In some embodiments, to optimize the stimulation of the target nerve and to avoid / minimize the stimulation of non-target nerves or anatomical structures, three or more emitters / electrodes (e.g., source and sink) may be combined to create a specially designed stimulation field shape.

[0147] When the energy source (emitter / electrode) extends less than 360° around the outside of the lead / cannula / sheath, the length of each emitter along the lead / sheath can typically be at least 0.5 millimeters, such as, for example, 0.5 to 6 millimeters. When the electrode extends 360° around the sheath, the length of the electrode along the sheath can typically be less than 6 millimeters, such as, for example, 0.5 to 6 millimeters or 1 to 4 millimeters. Devices and systems are contemplated herein that include emitters having various sizes and / or surface areas. For example, in some cases it may be desirable to have several large electrodes spaced apart from a small electrode to create a longer current path. In one example, the large electrode may serve as a current sink.

[0148] The stimulation leads described herein may use a flexible circuit that may include an array of conductors bonded to a thin flexible dielectric substrate. The dielectric substrate may include liquid crystal polymer (LCP), polyimide, and / or polyvinylidene fluoride. The conductors may include graphene, gold, silver, platinum, platinum-iridium alloy, iridium oxide, titanium nitride, tungsten, or combinations thereof. The conductors may be deposited on the dielectric substrate and then etched by chemical or laser ablation means to form an electrical circuit consisting of electrode pad contacts and traces that connect the pads to connectors. Additional materials may be deposited on the substrate (e.g., by sputtering or electroplating) to create discrete electrodes and / or insulating surfaces. In some embodiments, an integrated circuit may be attached to the substrate, such as by soldering, to provide a local smart circuit. The flexible circuit may have the advantages of being thin and flexible, which allows for high utility in medical applications. Multiple layers of the flexible circuit having several layers of conductive and insulating materials may allow for a three-dimensional structure of a more complex electrical network.

[0149] The stimulating electrode may be disposed at any position along the lead and may have various shapes, surface areas, and spacings. The stimulating lead may include at least one electrode, or may include two, three, four, five, or more electrodes. The electrodes may be spaced apart by about 1 mm to about 2 mm, about 2 mm to about 4 mm, about 4 mm to about 8 mm, or 8 mm or more. In some cases, a single electrode (or electrode pair) stimulates the target tissue. In some embodiments, two or more electrodes may be used to stimulate the tissue. In some situations, a subset of the electrodes, such as one or more electrodes disposed closest to the target location, may provide the stimulating energy. In such embodiments, the potential to stimulate non-target tissue, nerves, etc. may be reduced.

[0150] If an electrode close to the target tissue or nerve is selected, a relatively low level of energy may be used. The peak charge output of the lead can range from about 300 nC to about 6000 nC. The proximity characteristics of the electrodes help reduce the total amount of energy required to generate an action potential, thereby reducing the power consumption of embodiments that rely on battery power.

[0151] The device may include two or more channels of energy stimulation delivered to the nerve by electrodes disposed in the vicinity of the nerve and two channels of transvascular stimulation delivered to the nerve. The nerve can be partially or fully recruited by one or more energy sources disposed on the lead and / or one or more energy sources disposed on multiple leads. Partial nerve recruitment by one or more energy sources may be useful for reducing muscle fatigue over time. This can be achieved by alternating energy delivery through multiple energy sources. Alternatively, two or more different leads can be placed at different positions, both in the vicinity of the target nerve. Alternating stimulation between the energy emitters on the various leads can also provide the option of minimizing muscle fatigue and avoiding unwanted non-target nerve stimulation.

[0152] Figure 15 shows a block diagram of various components of the system. The lead may have any number of energy sources or sensors. The system may include a controller that can be part of any of the control units described herein. Each component of the system may be operatively coupled to the controller, and the controller may manage the operation of each energy source / sensor during nerve stimulation and control the collection of information by various sensors and electrodes.

[0153] It should be understood that the various modules described herein may be part of a computing system and are shown separately in Figure 15 for illustrative purposes only. The modules do not need to be physically separate.

[0154] The systems described herein may include, for example, an external respiratory assistance system (i.e., ERS, "pressure support"), a respiratory muscle stimulator (e.g., stimulator, stimulation lead, energy source, etc.), sensors (e.g., impedance sensor, pressure sensor, motion sensor, flow sensor, ultrasonic sensor, electrical sensor, thermal sensor, chemical sensor, optical sensor, etc.), a control unit, a processor, a controller (e.g., remote controller), cloud storage, a peripheral interface device, remote data storage, a data analysis unit, a data formatting unit, a data aggregation unit, and / or a computer. The components and electronic devices may include one or more processors (e.g., application processor (AP)), a communication module, a subscriber identification module (SIM), a memory module, a sensor module, an input device, a display, an interface, an audio module, a camera module, a power management module, a battery, an indicator, an alarm, a visual indicator, an optical indicator, and / or a motor.

[0155] The processor may include any suitable type of processing circuitry, such as one or more general-purpose processors (e.g., ARM-based processors), digital signal processors (DSPs), programmable logic devices (PLDs), application-specific integrated circuits (ASICs), and / or field-programmable gate arrays (FPGAs), etc. For example, the processor may include one or more of a central processing unit (CPU), an application processor (AP), and a communication processor (CP). The processor may perform, for example, calculations or data processing related to the control and / or communication of at least one other component of the system or related electronic devices. The processor may drive an operating system or an application program and control a plurality of hardware or software components connected to the processor by performing various data processing and calculations. The processor may be embodied, for example, as a system-on-chip (SoC). In one or more embodiments, the processor may further include a graphics processing unit (GPU) and / or an image signal processor. The processor can load commands or data received from at least one of the other components (e.g., non-volatile memory) into volatile memory, process the loaded commands or data, and store various data in non-volatile memory.

[0156] The control unit and / or one or more other processors may serve as a communication module and may also serve as a communication interface to other components of the system. An external respiratory assistance device such as a mechanical ventilator may also function as a communication module and / or a processor. The communication module may include, for example, a cellular module, a Wi-Fi module, a BT module, a GNSS module (e.g., a GPS module, a Glonass module, a Beidou module, or a Galileo module, etc.), an EEPROM module, and an RFID module, an NFC module, and / or a radio frequency (RF) module.

[0157] The system may include one or more data storage or memory components, which may include any suitable type of volatile or non-volatile memory such as random access memory (RAM), read-only memory (ROM), network-accessible storage (NAS), cloud storage, and / or solid-state drive (SSD). For example, the memory may include volatile memory and / or non-volatile memory. The memory may store, for example, commands or data related to at least one other component of the system or an electronic device including the system. According to one embodiment of the present disclosure, the memory can store software and / or programs within a controller such as a computer (e.g., a control unit). The programs may include, for example, a kernel, middleware, application programming interface (API), and / or application program (or "application"). At least some of the kernel, middleware, and API may be referred to as an operating system (OS).

[0158] The system may include one or more sensors as described herein. For example, the sensors may measure the physical state of a subject or the environment and / or detect the operating state of a connected electronic device. The sensors can convert the measured or detected information into an electrical signal. The sensors may measure / monitor, for example, impedance, respiration, airway pressure, gas distribution, air flow, CO2, O2, body temperature, blood glucose, heart rate, blood pressure, color, sound, and / or motion. The system may also include an electronic noise sensor, an electromyography (EMG) sensor, an electroencephalogram (EEG) sensor, an electrocardiogram (ECG) sensor, an infrared (IR) sensor, an iris scan sensor, a finger scan sensor, and / or other sensors disclosed herein or well-known in the art. The sensor module may further include a control circuit for controlling one or more sensors included therein. Further, the sensors may include, for example, at least one of a gesture sensor, a gyro sensor, an atmospheric pressure sensor (barometer), a magnetic sensor, an acceleration sensor, a grip sensor, a proximity sensor, a color sensor (e.g., a red, green, and blue (RGB) sensor), a biosensor (medical sensor), a temperature / humidity sensor, an illuminance sensor, and / or an ultraviolet (UV) sensor. Any of the individual electronic devices may further include a processor configured to control one or more sensor modules, either as part of the processor or separate from the processor, and may control the sensor modules while the processor is in a sleep state.

[0159] The system may include one or more input devices such as, for example, a touch panel / screen, a (digital) pen sensor, a remote control, a key, and / or other input devices. The touch panel may use, for example, at least one of a capacitive, resistive, infrared, and ultrasonic type. The touch panel may further include a control circuit. The touch panel or other elements of the input device may further include a tactile layer and may provide a tactile response to the user.

[0160] The system includes one or more input / output interfaces. The one or more input / output interfaces function as an interface that can transmit commands or data input from a user or another external device to other elements of the system or an individual device including the system. Further, the input / output interface can output commands or data received from other elements of the system or the electronic device to a user (e.g., a medical practitioner or a patient, etc.) or another external device.

[0161] The system of embodiments of the present disclosure may include one or more displays. Examples of the display may include a liquid crystal display (LCD), a light emitting diode (LED) display, an organic light emitting diode (OLED) display, a microelectromechanical systems (MEMS) display, and an electronic paper display. The one or more displays can communicate various types of content (e.g., text, image, video, icon, or symbol) to a user, for example. The display may include a touch screen and can receive touch, gesture, proximity, or hovering inputs using, for example, an electronic pen or a part of the user's body. The display may include a panel, a hologram device, or a projector. The panel can be mounted, for example, to be flexible, transparent, or wearable. The panel may be embodied as a single module having a touch panel.

[0162] The system may include one or more indicator / alarm / notification modules that can display a specific state of the system or an electronic device within the system (e.g., a booting state, a message state, a charging state, a treatment stage, a patient state, a warning, etc.). A motor or other suitable device may convert an electrical signal into mechanical vibration and can generate vibration, a tactile effect, etc. to notify a medical practitioner or a patient of an event or a situation. Although not shown, each electronic device / component may include a processing device (e.g., a GPU).

[0163] The energy source may be electronically coupled to a switching electronic device that can be communicatively coupled to a controller. The switching electronic device may include an application-specific integrated circuit, or other type of circuit that enables the controller to independently control the energy source of the stimulation array. A hub may also be connected to the switching electronic device and may be used as an energy source or an electrode or a sensor.

[0164] In some embodiments, the electrodes may be used for both electrically stimulating a target (e.g., a nerve and / or muscle) and collecting physiological information. When used for nerve or muscle stimulation, a first combination of electrodes (e.g., one, two, three, or more electrodes) may be electrically connected to a first stimulation module channel to stimulate a first nerve (e.g., the right phrenic nerve), and a second combination of electrodes on a different lead (e.g., one, two, three, or more electrodes) may be electrically connected to a second stimulation module channel to stimulate a second nerve (e.g., the left phrenic nerve). Electrical signals may be sent from the first and second stimulation module channels to the combination of electrodes to stimulate the nerve with the electrodes. In other examples, combinations of more than two electrodes may be used to stimulate one or more target nerves, and the system may include more than two stimulation module channels. Some electrodes may also be specialized for collecting physiological data (e.g., impedance, etc.). Some embodiments described herein may use energy sources and sensors that can be implanted in a patient, located outside the patient, or a combination of both.

[0165] The electrodes may further be configured to detect physiological information of a patient, such as nerve activity, ECG, or electrical impedance, respiration, etc., as described throughout the present disclosure. When used for detection, one or more of the electrodes may be electronically coupled to a signal acquisition module. The signal acquisition module may receive signals from the electrodes.

[0166] The switching electronic device may selectively couple the electrodes to the first stimulation module channel, the second stimulation module channel, or the signal acquisition module. In one example, any electrode can be used for nerve stimulation and any electrode can be used for the detection functions described herein. In other words, each electrode may be configured to stimulate a nerve, and each electrode may be configured to detect physiological information.

[0167] The signal acquisition module may further be coupled to one or more sensors configured to collect physiological information from the patient. For example, the system may include one or more of a blood gas sensor or a pressure sensor. These sensors may be located within the lumen of the stimulation lead, outside the patient in fluid communication with the lumen, on the outer surface of the catheter, or at any other suitable location. In one example, the blood gas sensor may be housed within the lumen or be fluidly connected, while the pressure sensor may be housed within the lumen or be fluidly connected. The blood gas sensor may measure the amount of O2 or CO2 in the patient's blood. The pressure sensor may measure the patient's central venous pressure (CVP).

[0168] Signals from the blood gas sensor can be transmitted to a blood gas signal processing / filtering module to be processed and filtered to determine blood gas levels. Signals from the electrodes, when they are used for detection, can be transmitted to a nerve signal processing / filtering module, an ECG signal processing / filtering module, or an impedance signal processing / filtering module as appropriate. Signals from the electrodes or other sensors can be transmitted to an amplification module, if necessary, to be amplified before the signals are transmitted to the appropriate processing / filtering module.

[0169] In one embodiment, the sensor can detect information from nerve signals and can be used to assist in the management of the delivery of treatment to a patient. For example, the electrical activity of respiratory muscles (e.g., diaphragm, intercostal muscles, etc.) and the vagus nerve signals from pulmonary stretch receptors can be used to optimize parameters related to the delivery of an external respiratory assistance system and / or a respiratory muscle stimulation system.

[0170] For patients with medium to high levels of consciousness, the electrical activity of the diaphragm can provide an accurate reflection of the patient's neural respiratory drive. In addition to this nerve signal, there are vagus nerve-mediated reflexes that detect lung stretch, which limit the amount of inspiration and thereby prevent overinflation (Hering-Breuer inflation reflex) and prevent contraction of the diaphragm during exhalation (Hering-Breuer deflation reflex).

[0171] The positive pressure provided by external respiratory assistance, the negative pressure provided by a stimulated respiratory muscle system, or both can be adjusted and coordinated to respond to the Hering-Breuer reflex nerve signal. For example, an increase in the amount of respiratory work provided by electrically stimulated respiratory muscles (e.g., negative pressure ventilation) can allow for a reduction in the positive pressure required by a ventilator. The reduction in positive pressure can reduce the likelihood of barotrauma or injury due to lung stretch.

[0172] The systems and devices described herein may include a blood oxygenation and / or CO2 removal device that processes a patient's blood to a predetermined level and adjusts blood gases. The systems described herein may also include at least one physiological sensor functionally connected to a control unit configured to acquire physiological data of the patient related to at least one of tidal volume, respiratory pressure, respiratory rate, respiratory work, CO2 saturation, oxygen saturation, body temperature, blood pressure, heart rate, blood oxygen concentration, and / or brain activity. The physiological data may be used to manage the distribution of gas / air within the patient's lungs during the respiratory cycle.

[0173] A system operating in A mode may include a closed-loop operation for autonomously stimulating respiratory muscles (e.g., diaphragm, intercostal muscles, etc.). This mode can utilize any patient response signal (feedback) that helps indicate the need for pacing. These signals include, but are not limited to, oxygen saturation, end-tidal CO2 (EtCO2), airflow, impedance, heart rate, motion-sensing accelerometer signal, or a combination thereof. In A mode, pacing may be performed continuously. An algorithm may be used to detect and / or modify the physiological response signal and determine whether changes to the stimulation pattern, frequency, respiratory rate, intensity, type, and / or shape profile are necessary to elicit the desired response.

[0174] FIG. 16 shows a flowchart of an exemplary process 1600 of a system operating in A mode. When a stimulus is initiated in A mode, the respiratory muscles can be stimulated to produce a desired physiological response (step 1601). A sensor may be used to monitor whether the desired physiological response has occurred. During stimulation, the system can monitor one or more impedance measurements (step 1602) and / or monitor the patient's physiological response (step 1603). Thereafter, the system can determine whether one or more impedance measurements and / or the patient's physiological response are within a predetermined range (step 1610). The predetermined range may be programmed by the user, by selected settings programmed into the system, and / or determined based on one or more measured characteristics, properties, or parameters. If the system determines that one or more impedance measurements and / or the patient's physiological response are within the predetermined range, the system can continue to stimulate the respiratory muscles to produce a desired physiological response (step 1601). If the system determines that one or more impedance measurements and / or the patient's physiological response are not within the predetermined range, before continuing to stimulate the respiratory muscles to produce a desired physiological response (step 1601), the system can change the programmed stimulation parameters (step 1620) and / or change the external respiratory assistance parameters (step 1630).

[0175] In some embodiments, the plurality of electrode leads may be fixed at a predetermined position of the phrenic nerve. A controller / stimulation / system may be used to determine the best set of electrodes for each hemidiaphragm. Determining the best set of electrodes may include finding the best combination of electrodes, which can be accomplished by transmitting signals through different combinations of electrodes on the plurality of electrode leads. This selection may be automated using feedback from sensors and / or involve feedback from medical personnel or other users. Once an electrode set is selected, the stimulation unit can go through a process of selecting the appropriate signal by varying the mode of the signal, such as current, and determining the response. If this process is automated, the system can transmit a series of signals and, based on the response from the sensor, determine which signal triggered the maximum response from the target respiratory muscle (e.g., the diaphragm, etc.). This may also be done manually by involving medical personnel or other users in determining the response from the muscle / nerve.

[0176] As described above, tissue impedance sensing (TIS) may be used to form tomographic images and / or analyze tissue state or composition. The system may be configured to adjust lung gas volume, pressure, and distribution between the left and right regions and between the anterior (upper) and posterior (lower) regions of the patient's lungs. Baseline measurements of lung gas distribution may be collected for regions including left anterior (LA), right anterior (RA), left posterior (LP), and right posterior (RP). A graphic display of one such exemplary distribution is shown in FIG. 17A. The specific 20%-30%-20%-30% distribution shown in FIG. 17A is one example, and other distributions are also conceivable. The display may be shown via an output device of the system or communicated to the user by other means. Based on the measured distribution or the generated display, one or more stimulation parameters and / or external respiratory assistance parameters can be varied to adjust the distribution of lung gas as described herein. The example of FIG. 17A showing two regions of two lungs is one example. Other configurations include calculating and displaying the lung gas distribution between the two lungs, as shown in FIG. 17B.

[0177] Additionally or alternatively, the amount of air that moves during each respiratory cycle (e.g., tidal volume), maximum airway pressure, plateau pressure, and / or pressure-time product may be measured. As described herein, other respiratory cycle characteristics and in some embodiments external respiratory assistance parameters may also be measured. Data regarding respiratory cycle characteristics may assist in adjusting the stimulation energy to balance pulmonary gas distribution.

[0178] Referring to FIG. 18A, an exemplary subject had a higher level of lung gas in the upper lung regions, and most of the lung gas had migrated to the upper right side. The tidal volume was lower than desirable, and the airway pressure was at the boundary with the higher side. The stimulation array was activated based on impedance and other sensor data collected. Referring to FIG. 18B, after the breathing and stimulation parameters were adjusted, the tidal volume visibly increased and the maximum airway pressure decreased to a safer range. A better balance of air was obtained between the upper and lower lung regions. Further adjustment of the respiratory muscle stimulator resulted in a better left - right lung gas balance as shown in FIG. 18C. The distribution of air within a quarter of the lung can be altered by delivering energy to the respiratory muscles or the nerves that control them. The distribution of air between the left and right lungs can be changed by altering the energy delivery to the left and / or right respiratory muscles. The distribution of air between the anterior and posterior lobes can be changed by stimulating different nerve axons of the nerve fibers by triggering another energy source (electrode) that controls different respiratory muscle fibers. The distribution of air between the anterior and posterior lobes can also be achieved by stimulating different intercostal or abdominal muscles at different intensities. The total amount of air in the lungs can be adjusted by changing the energy (e.g., total charge) delivered to the respiratory muscles and / or the nerves that control them. By balancing the work of the external respiratory assist device and the work done by the respiratory muscles, the lung gas and lung volume can be better distributed to reduce injury, improve patient comfort, repair the respiratory muscles, strengthen them, or exercise them. Sensors may be used to determine or detect whether the respiratory muscles are beginning to fatigue, and in these situations, the contribution of the work of the respiratory muscles may decrease and the contribution of the work of the external respiratory assist device may increase.

[0179] Referring to FIG. 19, a plurality of non-limiting exemplary situations are described where the delivery of energy to the respiratory muscles and / or the nerves controlling the respiratory muscles can lead to assisting the normal mucociliary action of the body, the generation of a cough, or the movement of fluid from the patient's airway. The waveforms described herein can induce a cough and the spontaneous movement of fluid within an individual's lungs by more physiological negative pressure ventilation, and in some cases, promote the movement of pulmonary fluid (secretions, mucus, mucus plugs, etc.). The respiratory muscles are stimulated by energy electro-hood envelopes that generate a response such as a cough by delivering energy that leads to a sudden contraction and gradual release of the respiratory muscles over a short period (in one embodiment, 1 to 3 seconds) as shown in FIG. 19(A1). The cough response can also be generated by gradually contracting the respiratory muscles over a short period (in one embodiment, 1 to 3 seconds) as shown in FIG. 19(A2), suddenly releasing the respiratory muscle contraction, or suddenly contracting the respiratory muscles as shown in FIG. 19(A3), maintaining it for a short period (in one embodiment, 1 to 3 seconds), and then suddenly relaxing the muscle. In some embodiments, such as those shown in FIGS. 19(A4) to 19(A6), a series of cough responses with small time gaps (e.g., 1 to 10 seconds) can be induced during a series of cough responses.

[0180] The respiratory muscles may contract gradually or suddenly. The muscle may maintain the contraction by a short-term fused contraction or relax immediately upon contraction. The muscle may relax gradually or suddenly. The charge may be modulated within a train of stimuli (multiple pulses) by modulating the amplitude (e.g., current or voltage), by modulating the pulse width, and / or by modulating the frequency of the pulse.

[0181] In some embodiments, a series of energy pulses may cause a twitch (single contraction, unfused contraction) of the respiratory muscles. The series of energy pulses can be delivered at a vibration frequency (e.g., 1 to 10 Hz) that aids the movement of fluid within the lungs. The series of energy pulses can be delivered multiple (e.g., 1 to 24) times a day for a short period (e.g., 1 to 10 minutes).

[0182] A medical practitioner, other user, or computer controller (e.g., in automatic mode) can modulate the stimulation energy, frequency, amplitude, and / or other parameters to achieve a desired effect (e.g., movement of respiratory secretions, mucus, and / or body fluids). Sensors described herein, such as impedance sensors, pressure sensors, volume sensors, and airflow sensors, can be used to evaluate the progress of secretions liberation therapy. In some embodiments, the RMS may be combined with external positive pressure therapy or external torso vibration therapy to achieve the desired effect. Associated muscle contractions, amplified vibrations, and / or increased inspiratory / expiratory pressures can, individually or collectively, lead to the relaxation and removal of respiratory secretions.

[0183] In some cases, a suction device can be used to assist in the removal of respiratory secretions. Devices and systems described herein that include a suction device can be inserted into a patient's lung to remove substances removed during and / or after the delivery of stimulation.

[0184] Respiratory secretions, including mucus and other fluids, can be readily exposed, removed, disrupted, released, and carried out of the patient using the methods and systems described herein. Removal of respiratory secretions can be associated with an increase in tidal volume, better gas distribution in lung regions, shortening of rehabilitation time, and other therapeutic benefits.

[0185] Delivery of electrical stimulation may be triggered in a plurality of ways. In one or more embodiments, a healthcare provider or other user operates a handheld controller. The controller can enable the operator to connect flexibly with the stimulation system, perhaps enabling the user to get closer to the subject. Such a controller can also enable the subject to control the delivery of stimulation. The controller can have its own controls or can be an extension of controls available at another interface within the stimulation system.

[0186] For manually triggered electrical stimulation, the remote controller may trigger the stimulation by pressing a button or another form of manual trigger by the operator. For electrical stimulation triggered by a closed-loop system, the remote controller may be used to initiate the closed-loop process or to interrupt this process.

[0187] In some embodiments, a closed-loop control system for triggering electrical stimulation delivery may be used. Such a closed-loop system automates the stimulation delivery process and removes errors due to the operator. One or more sensors can be used to determine when to trigger the stimulation delivery. An airflow that triggers the stimulation at the end-expiratory phase of the patient's respiratory cycle or another phase of the respiratory cycle can be measured. To trigger the stimulation at the end-expiratory phase of the patient's respiratory cycle or another phase of the respiratory cycle, a pressure sensor within the respiratory circuit may be used to determine which phase of the respiratory cycle the patient is in. An accelerometer, gyroscope, or other motion sensor can be used to detect the patient's respiration and trigger the stimulation at an appropriate phase of the patient's respiratory cycle. A CO2 sensor, O2 sensor, and blood gas sensor may be used to detect the patient's respiration and trigger the stimulation at an appropriate phase of the patient's respiratory cycle. To trigger the stimulation at the end-expiratory phase of the patient's respiratory cycle or other respiratory cycle phase, the central venous pressure may be used to determine the patient's current respiratory cycle phase.

[0188] To trigger the stimulation at the end-expiratory phase of the patient's respiratory cycle or another respiratory cycle phase, an impedance sensor may be used to measure lung function and determine which phase of the respiratory cycle the patient is in. Electrodes may be used to measure signals to the phrenic nerve to identify the location of the phrenic nerve during electrode placement.

[0189] In a closed-loop system, not only sensors but also control is required. Multiple controls can be used to determine when the system's response is needed. Stretch receptors may be used as controls for the stimulation charge or stimulation frequency (within and / or between pulse trains). Cognitive function sensors such as devices for measuring electroencephalogram, ECG, arousal, etc. may be used to monitor brain function. The work of breathing can be used as a control for the stimulation charge or frequency (within and / or between pulse trains). Airway or central venous pressure may be used as a control for the stimulation duration, stimulation intensity, or stimulation frequency (within and / or between pulse trains). Volume may be used as a control for the stimulation duration, stimulation intensity, or stimulation frequency (within and / or between pulse trains). Blood gas may be used as a control for the stimulation duration, stimulation intensity, stimulation frequency, or the frequency of rep delivery (within and / or between pulse trains).

[0190] Both the inspiratory and expiratory muscles can be stimulated, and each stimulation is coordinated to produce the desired respiratory result. As described herein, a higher stimulation level at a given stimulation frequency may be used to induce a cough response to assist in the movement of secretions within the patient's lungs.

[0191] The respiratory muscles such as the diaphragm may be exercised (reps) by initiating several contractions of the muscle. The reps can be initiated by patient involvement, electrical stimulation, other means, or a combination thereof. Each rep can have a contraction intensity, and based on the intensity of the contractions generated by the reps, the reps can range from weak to strong. The desired number of reps performed continuously is called a set. There may also be a waiting period (rest) between sets. The determination of reps, sets, and rest in an exercise regimen is considered a dosage. Different dosages are required for different patient parameters, conditions, and / or situations. The dosage examples disclosed herein are illustrative and can address the need to define dosages for exercising the diaphragm.

[0192] During surgery or in an intensive care environment, external respiratory assistance may be utilized. Under external respiratory assistance, the state and strength of the diaphragm rapidly decline. Diaphragm nerve stimulation or diaphragm pacing may be used to prevent said decline. When the diaphragm is stimulated about 60 to about 120 times a day, the strength of the respiratory muscles can be improved. Without being limited by theory, such stimulation can support the maintenance of an already strong diaphragm strength.

[0193] It may also be beneficial to stimulate the respiratory muscles more frequently (e.g., every few minutes / hour, about 5 to about 10 minutes / hour every few seconds, about 10 to about 20 minutes / hour every few seconds, or about 20 to about 50 minutes / hour every few seconds). Stimulating one or more respiratory muscles at the same frequency as diaphragmatic breathing or each breath can improve and / or maintain diaphragmatic muscle strength and reduce lung injury caused by positive pressure ventilation.

[0194] During surgery, stimulating the diaphragm every about 15 minutes, 20 minutes, 30 minutes, or 1 hour (e.g., intermittently) with about 5 to about 60 stimulus trains can maintain the strength of the diaphragm and also assist in reducing atelectasis and other lung injuries. When using electrical stimulation, the reps may be triggered manually by the operator, by direct triggering from a mechanical ventilator, by feedback from a sensor of the stimulation system, by an instruction from a controller, or by a combination thereof. In some embodiments, muscle fatigue may be measured to reduce overuse of the muscle.

[0195] Various treatment and exercise dosages and regimens are described in U.S. Patent Application Publication No. 2019 / 0175908, which is hereby incorporated by reference in its entirety.

[0196] The movement of the diaphragm can prevent the deterioration of the diaphragm and can be used in any situation where the patient is receiving respiratory assistance. Respiratory assistance can include, but is not limited to, PPMV, ECMO, ECCO2R, CPAP, and BiPAP. To prevent the deterioration of the diaphragm, the exercise dose of the diaphragm is ideally applied as soon as respiratory assistance is provided to the patient. Stimulating the diaphragm sometimes (e.g., every 1 to 3 breaths, every 1 to 10 minutes, or at a lower frequency, e.g., about 60 contractions every 3 to 8 hours) can prevent the deterioration of the diaphragm due to disuse. When using electrical stimulation, the stimulation train may be triggered manually by an operator, by a direct trigger from a mechanical ventilator, by feedback from a sensor of the stimulation system, or by a combination thereof.

[0197] The movement of the diaphragm can restore the deteriorated diaphragm and can be used in any situation where the patient is receiving respiratory assistance. In some embodiments, the diaphragm is already deteriorated and the stimulation is used to strengthen and repair the diaphragm. Such stimulation can be delivered in sets, and multiple stimulation trains (e.g., about 10 to about 30 stimulation trains) can be delivered in sets. Multiple sets can be delivered in sessions, e.g., about 2 to about 8 sets per session, and there is a rest period of about 1 to about 10 minutes between sets. Multiple sessions (e.g., 2 to 4) can be delivered in 24 hours. Other doses described herein can also be used to restore the diaphragm. When using electrical stimulation, the reps may be triggered manually by an operator, by a direct trigger from a mechanical ventilator, by feedback from a sensor of the stimulation system, or by a combination thereof.

Example

[0198] The following examples are intended to illustrate the present disclosure without essentially limiting it. It is understood that the present disclosure encompasses additional embodiments that are consistent with the foregoing description and the following examples.

[0199] Example 1 Eleven subjects were selected for testing using a respiratory muscle stimulation system. Each selected subject was an adult who had received positive pressure external respiratory assistance by a mechanical ventilator for at least 7 days. The overview of the test subject group is shown in Table 1 below.

[0200]

Table 1

[0201] Each subject was scheduled to receive 3 sessions of therapeutic respiratory muscle stimulation via the stimulation lead daily. Each session included 4 sets, with a 5-minute rest period between sets. Each set included 10 stimulation trains. The stimulation was delivered simultaneously to the left and right phrenic nerves at a frequency of about 15 Hz by a combination of quadripolar and bipolar electrodes. The amplitude of the stimulation was in the range of 0.1 mA to 13.5 mA and was delivered with a pulse width of about 200 μs to about 300 μs.

[0202] All 9 of the test subjects successfully received the catheter containing the stimulation lead, and the catheter was successfully removed from each subject. Furthermore, it was demonstrated that all subjects had successfully captured at least one phrenic nerve and showed respiratory muscle contraction in response to the stimulation. Most patients received most of the scheduled treatment, and each subject received an average of 10.2 days of stimulation sets. Finally, 7 subjects were successfully weaned from the mechanical ventilator. Of those who were not weaned, 1 left the study to receive a lung transplant, and the other chose not to continue mechanical ventilation on the 4th day of the study due to an existing undiagnosed disease.

[0203] The subjects showed improvement in maximal inspiratory pressure (MIP) and rapid shallow breathing index (RSBI). This led to a reduction in the duration of mechanical ventilator weaning and the length of stay in the ICU and hospital environment. The MIP and RSBI data are summarized in Tables 2 and 3, where the MIP and RSBI measurements at the start of the study (baseline) were compared with those at the time of scheduled continuous management.

[0204] [Table 2]

[0205] [Table 3] The above results suggest that the systems and methods described herein can be safely used in patients requiring mechanical ventilation. They appeared to improve the strength of the inspiratory muscles (as seen from the increase in MIP) and respiratory function (as indicated by the change in the RSBI score) in patients who had previously been dependent on mechanical ventilation. Furthermore, the systems described herein appeared to facilitate the successful weaning of patients who had required long-term mechanical ventilation.

[0206] Furthermore, the average change in MIP was plotted against the total number of respiratory muscle stimulation sessions. This plot is shown in Figure 20. As can be seen from Figure 20, the average change in MIP improved as more stimulation sessions were performed.

[0207] These data indicate that the systems and methods described herein (including those described in patents incorporated by reference) are safe and suitable for use as respiratory muscle stimulation systems in patients undergoing long-term mechanical ventilation. Furthermore, the systems and methods described herein may improve the weaning outcomes of patients who require long-term mechanical ventilation.

[0208] Example 2 Surprisingly, the stimulation therapy induced the movement of mucus and fluids in the subject's airway. The fact that the subject reported feeling a "pulling feeling", "traction feeling", and "hiccupping feeling" without pain indicates that respiratory muscle stimulation therapy may assist in the removal of fluids from the airway of patients receiving external respiratory assistance.

[0209] In at least one subject of the test described in Example 1, the movement of mucus plugs from the atelectatic lung base was observed. The mucus plugs were removed from the endotracheal tube via a bronchoscope. A 75-year-old white female subject with a 5-day history of mental status abnormalities and general weakness was admitted to the hospital. This subject was intubated due to acute respiratory failure and had started receiving broad-spectrum antibiotics. This subject's medical history was notable for extrinsic restrictive lung disease and the use of CPAP at home, as well as hypertension, chronic kidney disease, anemia, obesity, depression, and hyperthyroidism. Additionally, this subject had a long history of non-specific chronic weakness due to multiple unsuccessful diagnostic tests at external facilities.

[0210] The antibodies for myasthenia gravis were negative, and this subject was enrolled in the study after repeated failures of the spontaneous breathing test. Catheter insertion was completed without difficulty. The catheter placement was confirmed by chest x-ray. At the start of the study, this subject's MIP was -14.3 cmH2O. After up to three daily sessions of respiratory muscle stimulation therapy, this subject experienced two separate episodes of acute hypoxia due to the movement of mucus plugs.

[0211] During the first episode of hypoxia, this subject experienced respiratory distress due to a large mucus plug that had moved. This mucus plug was expectorated. After the removal of the moved mucus, this subject's respiratory status recovered. Positive pressure mechanical ventilation was increased overnight to assist in this subject's recovery.

[0212] Two days later, this subject exhibited a second episode of acute hypoxia and respiratory distress. This subject underwent a bedside fiberoptic bronchoscopy to remove a large, thick mucus plug located at the lower part of this subject's endotracheal tube. This mucus plug was removed by suction. Evaluation of both lungs revealed that the thin secretions in the lower lobes were gently aspirated. No obvious bleeding or endobronchial lesions were noted.

[0213] After removal of the mucus plug, this subject's external respiratory support was reduced daily, and this patient was weaned from mechanical ventilation on the 9th day. This subject's MIP improved to -18 cmH2O. This subject was successfully weaned from mechanical ventilation after 18 sessions of respiratory muscle stimulation and extubated on the 9th day after enrollment in the study. A summary of the patient's respiratory status over 9 days is shown in Table 4 below.

[0214]

Table 4

[0215] The results shown in Table 4 suggest that the systems and methods described herein can be safely used in patients requiring mechanical ventilation and can facilitate the movement and removal of fluid from the airway. In this case, the movement of mucus plugs is due to the increased strength and forced contractions of the diaphragm by pacing therapy, which enables the breakdown and removal of distal mucus plugs in the atelectatic lower lobes. This is demonstrated by a slight improvement in MIP and a decrease in pressure support. Specifically, the use of respiratory muscle stimulation therapy can assist the patient in achieving respiratory clearance by the movement of secretions in the lower airway. The removal of large mucus plugs can be facilitated by the atelectasis-based inflation, at least in part, by the systems and methods described herein. Close monitoring of these patients clearly showed that many require assistance (e.g., suctioning, etc.) if the movement of secretions results in temporary airway obstruction.

[0216] Example 3 As described above, atelectasis is a major cause of ventilator-induced lung injury in critically ill patients in a sedated state. Reducing atelectasis is a strategy for lung protection, but this can be difficult to achieve in passively breathing patients in a sedated state. Respiratory muscle stimulation therapy, when combined with mechanical ventilation, can provide a solution to this problem by maintaining the end-expiratory lung volume (EELV).

[0217] The progression of atelectasis can be measured in real time by observing changes in EELV using the non-invasive technique of electrical impedance tomography (EIT). Changes in local air volume alter the electrical impedance of lung tissue, which can be reconstructed and displayed as a series of images.

[0218] The study was conducted using a model of 50-kilogram pigs in a simulated ICU environment. The control group with only MV (n = 8) was given normal standard care and received positive pressure ventilation with the volume controlled at 6 - 8 mL / kg. The MV + stimulation group (n = 8) received respiratory muscle stimulation, which resulted in diaphragmatic contractions for each breath during the inspiratory phase of breaths triggered by the ventilator. For each subject, changes in EELV were recorded using EIT, comparing the first and final images of un-paced breaths, and the change in EELV was calculated.

[0219] Exemplary EIT images of the group with only MV are shown in Figure 21A. The first image is before MV is applied, and the second image is after 50 hours of MV. These EIT images show a loss of 1841 mL in EELV.

[0220] For comparison, the EIT images of the MV + stimulation group are shown in Figure 21B. The first image is before MV and stimulation are applied, and the second image is after 50 hours of MV and stimulation. These EIT images show a loss of 271 mL in EELV.

[0221] To ensure the same passive ventilation in both groups and rule out the effect of pacing, the un-paced breaths of the experimental group were compared with the breaths of the control group. The means were compared by a two-sided t-test, with a significance level of α = 0.5 and a significance level of β = 0.80. In the comparison of the first and last un-paced breaths in the MV + stimulation group, the mean reduction in EELV was 430 mL, showing a p = 0.005 compared to 1230 mL in the group with only MV over 50 hours of ventilation. This EIT analysis shows that there is 286% more atelectasis in the group with only MV. A box and whisker plot summarizing these results is shown in Figure 22.

[0222] Respiratory muscle stimulation therapy used in combination with MV significantly reduces the loss of EELV over 50 hours. EELV is a generally recognized measure of atelectasis, and the smaller amount in the MV+stimulation group reflects that more alveoli are available for ventilation. As atelectasis decreases, a larger and more uniform-shaped area is allocated for each tidal volume, promoting the maintenance of a more homogeneous distribution of ventilation. This is important because reducing atelectasis has many advantages, such as reducing atelectasis injury, decreasing the required ventilator driving pressure, and the possibility of early weaning from mechanical ventilation.

[0223] Example 4 As described above, the increased stress and strain due to atelectasis formation and barotrauma activate the inflammatory pathway, increase the levels of inflammatory cytokines, and enhance and perpetuate the lung injury process. Regarding the study of 50-kilogram pigs described in Example 3, bronchoalveolar lavage (BAL) of the right upper lobe of each subject was performed both before and after 50 hours of treatment. Samples obtained by bronchoalveolar lavage were analyzed for the levels of IL-1β, IL-6, and IL-8. IL-1β is a biologically active cytokine, and high serum levels are not only indicative of early acute lung injury in many cases but also predictors of poor clinical outcomes and strong inducers of pulmonary fibrosis. IL-1β causes the release of the pro-inflammatory cytokines IL-6 and IL-8. IL-6 and IL-8 levels are often high in the serum of patients with acute lung injury. Furthermore, high levels of these cytokines are often associated with poor clinical outcomes. The means were compared by a two-sided t-test, with a significance level of α = 0.5 and a significance level of β = 0.80. The results from the IL-6 and IL-8 assays are summarized in the box-and-whisker plots shown in FIGS. 23A, 23B, and 23C.

[0224] As seen in FIGS. 23A-23C, respiratory muscle stimulation therapy reduces the increase in inflammatory cytokines in the bronchoalveolar lavage fluid in the right upper lobe over 50 hours compared to mechanical ventilation alone. The overall IL-1β, IL-6, and IL-8 serum levels are significantly lower in the MV+stimulation group (n = 8) compared to the MV-only group (n = 8), indicating a reduction in systemic inflammation and a lower likelihood of secondary organ injury due to ventilator-induced lung injury. The reduction in the systemic levels of inflammatory cytokines in the MV+stimulation group indicates that the level of injury was low in this group because the lung compartments were preserved. Without being limited by theory, the reduction in atelectasis and barotrauma may result in a more homogeneous distribution of ventilation and a reduction in ventilator-induced lung injury. The significant difference in the inflammatory markers between the treatment group and the control group indicates that synchronous diaphragmatic contractions during controlled breathing help reduce lung inflammation in normal and healthy subjects.

[0225] In addition to measuring the cytokine levels described herein, the maximal inspiratory pressure, plateau pressure, and dynamic compliance of the subjects were measured during respiratory assistance by ERS (MV only) and during respiratory assistance by ERS with stimulation (MV+stimulation). In other words, the pressure and compliance of each subject were measured both during assisted breathing with stimulation and during breathing without assisted stimulation.

[0226] The maximal inspiratory pressure and plateau pressure data shown in FIGS. 24A-24C indicate that assisted breathing with stimulation includes a lower average maximal inspiratory pressure and a lower average plateau pressure compared to breathing without assisted stimulation.

[0227] Dynamic compliance is a measure of the ability of the respiratory system (e.g., the lungs and associated airways) to stretch, expand, or accept volume. Dynamic compliance can be measured by dividing the change in pressure of the respiratory system during air movement by the change in volume over that time frame. The compliance data shown in FIGS. 25A and 25B indicate that breathing assisted by stimulation resulted in a greater dynamic compliance compared to breathing assisted by ERS alone.

[0228] Example 5 To investigate how different types of diaphragmatic muscle fibers adapt to an increased work demand caused by respiratory muscle stimulation, a study was conducted using a model of 50-kilogram pigs. Positive pressure ventilation was applied to a control group with only MV (n = 4). The ventilation parameters were set to achieve a lung-protective volume, with a tidal volume of 8 mL / kg, positive end-expiratory pressure ventilation of 5 cmH2O, and FiO2 set to the minimum required to achieve adequate oxygenation. The pigs were placed in a deep sedated state by infusion of propofol, fentanyl, and midazolam, and a bolus dose of ketamine was administered to achieve an appropriate sedation level guided by bispectral analysis (BIS). Respiratory muscle stimulation was applied to the MV + stimulation group (n = 4), resulting in diaphragmatic contractions for each breath per second during the inspiratory phase of respiration triggered by the ventilator. The cross-sectional areas of various types of muscle fibers were compared between the two groups. Specifically, samples were excised from the left costal diaphragm of each subject to be euthanized later, clamped in their resting state prior to excision, and immediately stored for analysis.

[0229] The relative abundance of each muscle fiber type by cross-sectional area in each treatment group is shown in Table 5 below.

[0230] [Table 5] Type I muscle fibers are slow muscle fibers and may be called slow oxidative fibers. They have a slow contraction time after electrical stimulation and generate less force compared to type 2 muscle fibers. Slow muscle fibers can be recruited at a lower stimulation threshold than other muscle fiber types. Type I muscle fibers are used for sustained low-level activity and are equipped with a large number of large mitochondria and relatively abundant intracellular lipids for oxidative metabolism.

[0231] Type II muscle fibers are fast muscle fibers and may be called fast glycolytic fibers. They have a rapid contraction time after stimulation. Type II muscle fibers are recruited at a higher threshold stimulus than type I muscle fibers and are used for short-term, high-intensity activities and for carrying heavy loads. Some type II muscle fibers are specialized for anaerobic metabolism, may contain smaller and fewer mitochondria, store less lipid, and have a larger glycogen storage compartment than type I fibers.

[0232] Type II fibers are divided into type IIA and type IIX fibers. Both of these fibers have a high contraction speed and, therefore, generate greater force compared to type I fibers. Type IIA fibers have a moderately high contraction speed and are essentially anaerobic. Type IIA fibers also have a high density of mitochondria and are highly oxidizable. Type IIb fibers have a very high contraction speed and are essentially anaerobic. In mammals, type IIA fibers mainly contain the myosin isoform Myh2, and type IIb fibers have a low mitochondrial density and mainly contain the myosin isoform Myh4.

[0233] For example, increasing type I muscle fibers at the expense of type IIX muscle fibers during respiratory muscle stimulation can contribute to an increase in the endurance of respiratory muscles. The cross-sectional area of the muscle fibers identified for each left costal diaphragm sample was measured. The area was normalized to the weight of the sample and graphed in FIGS. 26A - 26C. The Mann-Whitney U test statistic was used to determine the level of significance of the difference between the two groups. The normalized pooled mean cross-sectional area, along with the p-value from the Mann-Whitney U test, is summarized in Table 6 below.

[0234]

Table 6

[0235] The principles, representative embodiments, and modes of operation of the present disclosure have been described in the foregoing specification. However, the aspects of the present disclosure that are intended to be protected should not be construed as being limited to the specific embodiments disclosed. Furthermore, the embodiments described herein should be considered illustrative rather than restrictive. It will be understood that modifications and changes may be made by others without departing from the spirit of the present disclosure, and equivalents may be used. Accordingly, it is clear that all such modifications, changes, and equivalents are within the spirit and scope of the present disclosure as claimed.

[0236] In some embodiments, a system for stimulating tissue may include a stimulation device, an impedance sensor, and a control unit. The control unit receives an impedance signal from the impedance sensor, determines a first value of a lung gas parameter based on the impedance signal, compares the first value with a predetermined value of the lung gas parameter, determines one or more first stimulation parameters based on the comparison of the first value and the predetermined value, and is configured to deliver a stimulation signal including the one or more first stimulation parameters to the tissue via the stimulation device.

[0237] The systems described herein may include any of the following features. The system for tissue stimulation may further include an external respiratory assistance device and / or a remote controller. The control unit may further be configured to receive an adjustment signal from the remote controller and, upon receiving the adjustment signal, deliver a second stimulation signal including one or more second stimulation parameters to the tissue via the stimulation device. The control unit may further be configured to adjust the pressure or volume supplied by the external respiratory assistance device and / or generate an image corresponding to the distribution of air between regions of the lungs based on a comparison of a first value with a predetermined value. The image may be generated based on an impedance signal. The one or more first stimulation parameters may include one or more of duration, pulse width, frequency, amplitude, or a combination thereof. The control unit may communicate wirelessly with the stimulation device or the impedance sensor. The stimulation device may include two or more electrodes supported by a tubular member and / or the impedance sensor may be supported by the tubular member. The flexible circuit may be attached outside the tubular member and connected to the two or more electrodes and the impedance sensor. The pulmonary gas parameters may correspond to the distribution of air between regions of the lungs, and the distribution of air between regions of the lungs may include the distribution of air between the posterior and anterior regions of the lungs, the distribution of air between the upper and lower regions of the lungs, and / or the distribution of air between the right and left lungs. The pulmonary gas parameters may correspond to one or more lung volumes. The tissue may be a first tissue, and the impedance sensor may be part of an array of impedance sensors, and the array may be configured to be attached to a second tissue proximate to the first tissue. The impedance signal may be a first impedance signal, the stimulation signal may be a first stimulation signal, and the control unit may further receive a second impedance signal, determine a second value of the pulmonary gas parameters based on the second impedance signal, compare the second value of the pulmonary gas parameters with the first value of the pulmonary gas parameters or a predetermined value of the pulmonary gas parameters, and be configured to determine one or more second stimulation parameters based on a comparison of the second value with the first value or the predetermined value.

[0238] The technical idea that can be grasped from the above-described embodiment will be described below. [Appendix 1] A system for stimulating tissue, a stimulation device including electrodes configured to deliver energy to the tissue of a subject, an impedance sensor including electrodes configured to acquire an impedance signal from the subject, and a control unit, wherein the control unit receives the impedance signal from the impedance sensor, determines a first value of a lung gas parameter characterizing the dynamic respiratory state of the subject based on the impedance signal, compares the first value with a predetermined value of the lung gas parameter, determines one or more first stimulation parameters based on the comparison between the first value and the predetermined value, and is configured to deliver energy corresponding to a stimulation signal including the one or more first stimulation parameters to the tissue via the stimulation device, wherein the lung gas parameter includes the distribution of air between regions of the lungs of the subject, and the distribution of air between regions of the lungs includes at least one of the air distribution between the posterior and anterior regions of the lungs, the air distribution between the upper and lower regions of the lungs, and the air distribution between the right and left lungs, a system. [Appendix 2] The system according to Appendix 1, further comprising an external respiratory assistance device functionally connected to the control unit and configured to send gas to the lungs of the subject. [Appendix 3] The system according to Appendix 2, wherein the control unit is further configured to adjust the pressure or volume of the gas supplied to the lungs of the subject by the external respiratory assistance device based on the comparison between the first value and the predetermined value. [Appendix 4] The tissue is the first tissue, the impedance sensor is part of an array of impedance sensors, the array comprises attachment means for fixing the array to the subject, and the array is configured to be attached to a second tissue proximate to the first tissue, the system according to any one of appendices 1 to 3. [Appendix 5] The system further comprises a display functionally connected to the control unit, The control unit is further configured to analyze the impedance signal to generate, on the display, an image corresponding to the distribution of air between regions of the lungs of the subject, the system according to any one of appendices 1 to 4. [Appendix 6] The one or more first stimulation parameters include one or more of duration, pulse width, frequency, amplitude, or a combination thereof, the system according to any one of appendices 1 to 5. [Appendix 7] The impedance signal is a first impedance signal, the impedance sensor is further configured to obtain a second impedance signal from the subject, the stimulation signal is a first stimulation signal, and the second impedance signal is a signal obtained after delivering energy corresponding to the first stimulation signal to the tissue, The control unit, Receives the second impedance signal, Determines a second value of the lung gas parameter based on the second impedance signal, Compares the second value of the lung gas parameter with the first value of the lung gas parameter or the predetermined value of the lung gas parameter, Determines one or more second stimulation parameters based on the comparison of the second value with the first value or the predetermined value, The system is further configured to deliver, via the stimulation device, energy corresponding to a second stimulation signal including the one or more second stimulation parameters to the tissue, the system according to any one of appendices 1 to 6. [Appendix 8] The system according to any one of Appendices 1 to 7, wherein the control unit wirelessly communicates with the stimulation device or the impedance sensor. [Appendix 9] Further including a remote controller, The impedance signal is a first impedance signal, the impedance sensor is further configured to obtain a second impedance signal from the subject, the stimulation signal is a first stimulation signal, and the second impedance signal is a signal obtained after delivering energy corresponding to the first stimulation signal to the tissue. The control unit, Receives the second impedance signal, Based on the second impedance signal, determines a second value of the pulmonary gas parameter, Compares the second value of the pulmonary gas parameter with the first value of the pulmonary gas parameter or the predetermined value of the pulmonary gas parameter, Based on the comparison between the second value and the first value or the predetermined value, determines one or more second stimulation parameters, Receives an adjustment signal from the remote controller, When receiving the adjustment signal, further configured to deliver, via the stimulation device, energy corresponding to a second stimulation signal including the one or more second stimulation parameters to the tissue, the system according to any one of Appendices 1 to 6 and 8. [Appendix 10] The stimulation device includes two or more electrodes supported by a tubular member, and the impedance sensor is supported by the tubular member, the system according to any one of Appendices 1 to 3 and 5 to 9. [Appendix 11] The flexible circuit is attached outside the tubular member and is connected to the two or more electrodes and the impedance sensor, the system according to Appendix 10. [Appendix 12] The distribution of air between regions of the lung of the subject includes the ratio of air in regions of the lung of the subject, the system according to any one of Appendices 1 to 11. [Appendix 13] The system according to any one of Appendices 1 to 12, wherein the lung gas parameter further includes one or more lung volumes of the subject.

Claims

【Claim 1】 The device described in the specification.

Images