Devices for the prevention, mitigation, and / or treatment of cognitive impairment

Abstract

To provide a method and a system for preventing, mitigating, and / or treating brain damage.SOLUTION: A method includes: acquiring a test result reflecting a state of an object brain; determining a stimulation parameter on the basis of the test result; and stimulating nerves on the basis of the stimulation parameter. By stimulating the nerves, contraction of an object respiratory muscle is assisted or caused. A system can include: a processor configured to receive the test result reflecting the state of the object brain, and to determine the stimulation parameter on the basis of the test result; and a stimulator configured to stimulate the nerves on the basis of the stimulation parameter. By stimulating the nerves, contraction of an object respiratory muscle is assisted or caused.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 527,536, filed Jun. 30, 2017, the entire disclosure of which is incorporated herein by reference in its entirety.

[0002] In general, all publications, patent applications, and patents mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0003] Embodiments of the present disclosure generally relate to methods, systems, and devices for the diagnosis, alleviation, and treatment of cognitive impairments (e.g., delirium induced by mechanical ventilation, stroke, concussion, etc.). In some examples, the present disclosure relates to methods for reducing the occurrence of injury or brain death of a subject's brain cells. One representative aspect relates to methods for reducing the occurrence of injury or brain death of brain cells caused by a temporary cerebral hypoxia / ischemia condition, an inflammatory condition of the brain, or a traumatic brain injury (TBI) event. Another representative aspect relates to devices, systems, and methods for reducing brain and / or cognitive impairment in patients on mechanical ventilation. Yet another representative aspect relates to alleviating diaphragmatic muscle injury, lung injury, and brain injury.

Background Art

[0004] Patients undergoing life-saving treatment, particularly those requiring invasive mechanical ventilation (MV), often experience higher levels of diaphragmatic, lung, brain, and other organ damage. The diaphragmatic muscles may rapidly lose muscle mass and strength. The lungs may be traumatized by the ventilator. Cognitive impairment can be triggered by several factors, including abnormal neuronal signaling and inflammatory responses. Patients with pre-existing cognitive impairment, such as from traumatic (e.g., concussion) or ischemic (e.g., stroke) brain events, may be at even greater risk of rapid cognitive decline once MV is performed. There is a need for cost-effective, practical, surgically simple, and minimally invasive devices and methods that can reduce diaphragmatic, lung, and cognitive impairment (e.g., delirium, dementia, and cognitive dysfunction) in ICU patients, especially those undergoing MV.

[0005] During spontaneous breathing, the diaphragm and other respiratory muscles contract, creating a negative pressure area outside the lungs. The lungs expand to equalize the pressure, and air flows naturally into the lungs. This flow of air into the lungs is called inhalation (the act of breathing in). Most ventilators use positive pressure to periodically pressurize and / or inflate the lungs, assisting the patient's breathing by aiding in the inhalation of oxygen and the exhalation of carbon dioxide into the lungs. While life-saving in many ways, MV can also be harmful.

[0006] For example, ventilator-induced lung injury (VILI) can induce ventilator-induced lung injury (VILI), including volume injury, atelectasis injury, and biological injury. Volume injury is damage from overinflation of the lung parenchyma, which may result from high tidal volume and / or low lung compliance. Atelectasis injury may result from the opening-collapse of collapsed alveoli during each ventilator cycle, generally as a result of low tidal volume (Vt), low pressure, or insufficient levels of positive end-expiratory pressure (PEEP). Biological injury is the manifestation of a local inflammatory process, which may be characterized by the release of inflammatory mediators due to overinflation tidal volume and repeated opening and closing of unstable lung units.

[0007] Lung injury can lead to the activation of inflammatory genes and the release of inflammatory mediators from lung cells. Periodic stretching (CS) of lung tissue can result in inflammatory cell infiltration (which may contribute to the loss of capillary-alveolar barrier function), increased expression of pro-inflammatory mediators including tumor necrosis factor-α and IL-6, and induction of cell apoptosis. When free inflammatory mediators from the lungs circulate through the body's organs, they can impair oxygen supply and potentially lead to organ failure. MVs can contribute to the localization of pulmonary inflammatory responses, leading to multiple organ failure syndrome. Therefore, MV-induced lung stress and tension can result in alveolar inflammatory responses, a gradual increase in neutrophils in the lung parenchyma, and cytokine production. This process can then spread into the intravascular circulatory system and potentially reach distal organs (e.g., the brain).

[0008] Furthermore, the lungs can sense mechanical stimuli induced by MVs through mechanoreceptors, and the lungs can transmit this information to the brain via the autonomic nervous system. The diaphragm has important sensory innervation.

[0009] Typically, the purpose of mechanical ventilation is to provide precise control of respiratory variables (e.g., control of arterial oxygen (PaO2) and arterial carbon dioxide (PaCO2) partial pressures). Ventilators can provide effective gas exchange by periodically applying pressure to the lungs. It is important to balance the objectives of minimizing lung distension with minimizing lower lung collapse. Each patient's unique lung volume, lung compliance, and gas exchange requirements can make these objectives difficult.

[0010] A reduced tidal volume can lead to hypercapnia (increased PaCO2). Hypercapnia can lead to increased intracranial pressure. Improved systemic oxygen saturation can reduce hypoxic brain injury. However, excessively high ventilator pressure can lead to a systemic inflammatory response, thus affecting brain oxygenation and metabolism, and potentially inducing brain damage.

[0011] PEEP can be used to release previously collapsed alveoli, improve arterial oxygenation, and reduce the elasticity of the respiratory system. However, PEEP can also be detrimental to gas exchange, reducing cardiac output by decreasing aortic blood flow / pressure, which can lead to barotrauma.

[0012] Prophylactic ventilation at moderate to low tidal volumes (e.g., 6 mL / kg), limited to a plateau pressure <30 cmH2O and utilizing 10 cmH2O versus high Vt PEEP and no PEEP, can result in less pneumonia and a lower mortality rate. However, no single ventilation method is suitable for all scenarios. Even for a single patient, balancing diaphragmatic protection, lung protection, and brain protection while providing adequate gas exchange can be challenging. Therefore, clinicians may have to use a balanced approach that compromises the possibility of damage to one organ while reducing the possibility of damage to another.

[0013] Therefore, the need remains to limit or reverse lung damage in mechanically ventilated patients.

[0014] While MV (measuring tube) can be a life-saving intervention for patients with respiratory failure, prolonged MV can promote diaphragmatic atrophy and dysplasia (VIDD). This type of diaphragmatic injury and associated diaphragmatic atrophy can be a contributing factor to the difficulty in removing the MV.

[0015] The vast majority of patients treated with MV are immediately freed from ventilator support upon recovery from respiratory failure or surgery, but nearly one-third of patients face challenges in regaining the ability to breathe spontaneously. The prognosis may be good for patients who successfully discontinue MV on the first attempt, but poor for the rest.

[0016] To date, the need to limit or reverse diaphragmatic damage in mechanically ventilated patients has not been met.

[0017] The diaphragm is a central source of information for the entire body. In addition to functioning as a primary respiratory muscle, it is involved throughout the body as part of the information network necessary for respiration. The diaphragm has important sensory innervation. Both the phrenic and vagus nerves are part of this network, each containing sensory and motor fibers. For example, the vagus nerve, which innervates the lower leg portion of the diaphragm, can directly affect the reciprocal tension membrane (e.g., the dura mater) system, which gives rise to various related symptoms in the body. Through a similar mechanism, events of diaphragmatic dysfunction can result in a cascade of signaling events that affect the brain and other organs. Because both the vagus and phrenic nerves innervate the diaphragm, stimulation of either the vagus or phrenic nerve can affect other signaling cascades. The potential implications of stimulation of the brain, other organs and tissues of the body will be discussed further below.

[0018] Both delirium and cognitive impairment occur in as many as 87% of patients in the intensive care unit (ICU) when they are provided via invasive mobile ventilator (MV) in conjunction with lung support (Ely EW et al., "Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU)," JAMA, 2001). Despite advances in treatment methods, delirium and cognitive impairment remain major problems for MV patients.

[0019] Abnormal nerve signaling can lead to neuronal, cellular, and inflammatory processes, which can result in cognitive impairment during and after mechanical ventilation treatment.

[0020] Vagus nerve resection in subjects undergoing vagus motility (MV) can mitigate the increase in dopamine synthesis enzyme concentration and the degree of apoptosis in hippos compared to control animals. This suggests that the vagus nerve sends signals (related to MV) that trigger dopamine increases.

[0021] Patients receiving life-saving treatment with pre-existing brain injury (e.g., stroke, TBI, acute ischemia, etc.) and on mechanical ventilation are at increased risk of long-term cognitive impairment. Therefore, there is a need for effective preventive or neuroprotective treatments for humans.

[0022] Inflammation is a common pathological mechanism of acute lung injury and acute brain injury, affecting brain homeostasis. While the inflammatory cascade after acute brain injury may adversely affect the lungs, evidence suggests the reverse can occur as well. This can arise from complex interactions between the autonomic nervous system, neuroinflammation, neuroendocrine, and immunological pathways, which are physiologically programmed to preserve systemic homeostasis but can, in certain circumstances, cause adverse effects on distant organs and systems.

[0023] The lungs sense mechanical stimuli through mechanoreceptors, and this information is transmitted to the brain via the autonomic nervous system. The afferent vagus nerve transmits information from lung stretch receptors to the respiratory center in the brain. To date, there is a need for effective treatments to help treat or alleviate both brain and lung damage.

[0024] Afferent and efferent vagus nerves, α7 nAChR-expressing inflammatory cells, and the central vagal nucleus in the brain form inflammatory reflexes that can control inflammation and immunity. Sensory nerves can detect pathogens, injuries, or damage via peripheral afferent vagal nerve endings and then provide feedback to the nucleus tractus solitarius (NTS) in the brainstem. The information is processed, and the efferent vagus nerve can transmit the integrated information via action potentials to the celiac ganglion and then to other parts of the body.

[0025] The vagus nerve originates from the medulla oblongata and consists of four nuclei: the dorsal nucleus, nucleus ambiguus, NTS (Nutrition Transit System), and trigeminal spinal nucleus. Nearly 80% of afferent sensory fibers are contained within the vagus nerve and are involved in transmitting information to the NTS. Numerous afferent vagus nerve endings are located in the lungs and diaphragm. For example, lung information is transmitted to the NTS (processing center) via afferent pathways, which can distinguish between types of infection, inflammation, or injury. Vagus nerve endings can synthesize and release Ach, thereby activating α7 nAChR in pro-inflammatory cells (e.g., macrophages and neutrophils or epithelial cells) and regulating the production of pro-inflammatory cytokines via NF-KB.

[0026] One mechanism of transient ischemic protection involves the afferent vagal pathway. The vagus nerve consists of both afferent and efferent fibers, which account for 80% of the afferent impulses generated in the thoracic and abdominal organs. Afferent activity is relayed to the vagal septum (NTS), which has projections to the locus coeruleus (LC), controlling the release of norepinephrine (NE) and 5-hydroxytryptamine (5-HT). NE, activated by the VNS, can have anti-inflammatory effects and can stimulate the release of 5-HT. Data showing that 5-HT agonists can reduce glutamate release in cerebral ischemia suggest that 5-HT attenuates excitotoxicity by inhibiting glutamate release. The effects of these afferent pathways can contribute to the effects of transient ischemic protection (NVS) in cerebral ischemia. Alternatively, the efferent vagal pathway can also induce neuroprotection via the cholinergic anti-inflammatory pathway (CAP), which is activated by the brain's central cholinergic system via the efferent fibers of the vagus nerve.

[0027] Electrical stimulation of the vagus nerve, which leads to CAP activation, can suppress brain inflammation and provide neuroprotection against ischemic stroke. Efferent vagus nerve stimulation can also inhibit the localized inflammatory cytokine cascade of tissues and organs innervated by efferent vagus nerve fibers.

[0028] When activated, resident macrophages (microglia) in the central nervous system (CNS) can secrete molecules that cause neurological dysfunction or degeneration. It has further been found that stimulation of the efferent vagus nerve fibers releases sufficient acetylcholine to mitigate systemic cytokine cascades, such as those that occur in endotoxin shock, or local cytokine cascades.

[0029] Vagus nerve stimulation may result in upregulation (expression) of the α7 nAChR. Anti-inflammatory cellular and molecular mechanisms may be partly attributable to acetylcholine (Ach), a neurotransmitter mainly released from vagus nerve terminals. Activation of the α7 nAChR by Ach in macrophages suppresses the release of pro-inflammatory cytokines in the peripheral circulation, thereby preventing tissue damage via the inflammatory reflex of the VN. The α7 nAChR receptor is normally expressed in the brain, including neurons, glial cells, and endothelial cells. Activation of these receptors can enhance neuronal resistance to ischemic or other types of disorders.

[0030] Alternative techniques for stimulating neural tissue without requiring invasive procedures are transiently interfering stimuli, including crossing two high-frequency electrical signals in a specific brain region to be stimulated. The two signals interfere with each other and become a low-frequency signal in the target region. The low-frequency signal can induce and excite neurons, while the high-frequency signal cannot, so the surrounding tissue is not activated, but the target region can be activated. SUMMARY OF THE INVENTION

[0031] Embodiments of the present disclosure relate, inter alia, to systems, devices, and methods for preventing, alleviating, and / or treating brain injury. Each embodiment disclosed herein can include one or more features described in connection with other disclosed embodiments.

[0032] This disclosure includes a method for treating a subject. In some embodiments, the method may include: obtaining a test result that reflects the state of the subject's brain; determining stimulation parameters based on the test result; and stimulating a nerve based on the stimulation parameters, thereby assisting or causing contraction of the subject's respiratory muscles by nerve stimulation. In some examples, the nerve may be the phrenic nerve, and the respiratory muscle may be the diaphragm muscle.

[0033] In some cases, the nerve may be the first nerve, and the method may further include stimulating the second nerve, thereby eliciting a biological response in the brain that reduces the level of factors contributing to brain damage. The second nerve may be the vagus nerve. Stimulation of the second nerve can affect signaling from the second nerve of the subject to the brain or lungs. The method may further include stimulating the third nerve. In this case, the second nerve may be the left vagus nerve, and in some cases the third nerve may be the right vagus nerve, and the nerve may be the first nerve, and the method may further include inhibiting the transmission of abnormal signals by the second nerve.

[0034] In some cases, the vagus nerve can be stimulated by a nerve stimulator. For example, the vagus nerve can be stimulated by an external nerve stimulator. The external nerve stimulator can be placed in a skin area adjacent to the vagus nerve in question. Alternatively, the vagus nerve can be stimulated by an implantable nerve stimulator. The vagus nerve can be stimulated by manual, mechanical, electrical, ultrasonic, or electromagnetic energy.

[0035] In some cases, the test results are based on imaging the brain. Alternatively, the test results may include the concentration of inflammation-related or pain-related proteins in the subject's blood. The method may further include performing a test that provides test results.

[0036] In some cases, stimulating a nerve may include inserting a catheter equipped with one or more electrodes into a target blood vessel and positioning one or more electrodes in close proximity to the nerve.

[0037] In some cases, the method may further include artificially resuscitating the subject with a ventilator. In such cases, the test results may include the effect of artificial respiration on the brain. The method may further include stimulating the second nerve during at least a portion of the inspiratory period of artificial respiration.

[0038] In some embodiments, a method for treating a subject may include stimulating a first nerve with a first stimulator to assist or induce contraction of the subject's respiratory muscles; and stimulating a second nerve with a first or second stimulator to reduce the level of factors causing brain damage. The method may further include stimulating a third nerve with a first, second, or third stimulator to assist or induce contraction of the subject's respiratory muscles. Factors causing brain damage may also be inflammation of the brain. The first nerve may be the phrenic nerve, and the second nerve may be the vagus nerve. The respiratory muscles may be the diaphragmatic muscles.

[0039] In some cases, stimulation of the first nerve may occur simultaneously with stimulation of the third nerve. Alternatively, stimulation of the first nerve may be coordinated with stimulation of the second nerve. Stimulation of the first nerve may occur simultaneously with stimulation of the second nerve.

[0040] In some cases, the method may further include artificially respiration to the subject using a ventilator. The second nerve may be stimulated during at least a portion of the inspiratory period of artificial respiration.

[0041] In some cases, stimulation of the second nerve can be performed while the first nerve is not stimulated by the first stimulator. The first stimulator may include an intravascular catheter having a pair of electrodes configured to stimulate the phrenic nerve. The second stimulator may include an intravascular catheter having a pair of electrodes configured to stimulate the vagus nerve.

[0042] In some embodiments, a method for treating a subject may include: stimulating a first nerve with a stimulator to assist or induce contraction of the subject's respiratory muscles; obtaining test results of the subject's vagus nerve activity; creating stimulation parameters based on the test results; and stimulating at least one of the first and second nerves based on the stimulation parameters. The second nerve may be the vagus nerve, and stimulating at least one of the first and second nerves based on the stimulation parameters may include stimulating the second nerve based on the stimulation parameters. The first nerve may be the first phrenic nerve, and the second nerve may be the second phrenic nerve. In some cases, test results may be obtained by testing cardiac blood flow, testing peripheral blood flow, testing blood pressure, and imaging or evaluating molecules related to inflammation or pain in the subject's blood.

[0043] This disclosure also includes a system. In some embodiments, the system may include: a processor configured to receive test results reflecting the state of a subject's brain and to determine stimulation parameters based on the test results; and a stimulator configured to stimulate nerves based on the stimulation parameters, thereby assisting or causing contraction of the subject's respiratory muscles by nerve stimulation. The system may further include a ventilator. The system may further include one or more switches operablely connected to the processor, the one or more switches configured to control the stimulation output to the stimulator.

[0044] In some examples, the system may further include sensors configured to detect cardiac events, respiratory events, catheter location, blood pressure, or levels of inflammatory substances. A stimulator can be connected to the sensors. The stimulator may include an intravascular catheter having a first set of electrodes configured to stimulate the right phrenic nerve and a second set of electrodes configured to stimulate the left phrenic nerve. The stimulator may be configured to affect phrenic nerve signaling, vagus nerve signaling, or a combination thereof.

[0045] In some embodiments, the system may include electrodes configured to stimulate a first nerve to assist or cause contraction of a target respiratory muscle, and a stimulator configured to stimulate a second nerve to reduce the level of factors contributing to brain damage. The stimulator may include an intravascular catheter having one or more electrodes configured to stimulate the vagus nerve. The system may further include a catheter configured for intravascular insertion, the catheter comprising a first plurality of electrodes and a second plurality of electrodes.

[0046] In some embodiments, the system may include: a first nerve stimulator configured to stimulate a first nerve, thereby assisting or causing contraction of the respiratory muscles of a subject by stimulation of the first nerve; a processor configured to receive test results of vagus nerve activity of a subject and to generate stimulation parameters based on the test results; and a second nerve stimulator configured to stimulate a second nerve based on the stimulation parameters.

[0047] The accompanying drawings, incorporated herein and part thereof, illustrate non-limiting embodiments of this disclosure and, together with the detailed description, illustrate the intent of this disclosure. [Brief explanation of the drawing]

[0048] [Figure 1]This shows the structure of selected nerves, tissues, and blood vessels in the human neck, brain, lungs, and upper torso. [Figure 2] Exemplary embodiments include selected nerve and vascular structures of the human neck and upper torso, diaphragmatic and intercostal respiratory muscles, a typical stimulator (e.g., a catheter) placed in one vein, a control device, sensors (e.g., motion sensors, airflow sensors, and / or pressure sensors), a typical remote control device, a graphical user interface, a pulse generator, and an external respiratory support device. [Figure 3] In addition to the control device, the diagram shows the selected nerve and vascular structures of the human neck and upper torso, along with a first representative stimulator (e.g., a catheter) placed at a first position (e.g., a vein, artery, skin, etc.) and a second representative stimulator (e.g., a catheter) placed at a second position (e.g., a vein, artery, skin, etc.). [Figure 4A] An exemplary embodiment shows a ventral view of a pair of representative catheters having windows that can be positioned to align with nerve stimulation electrodes within the catheter, where the representative catheters are inserted into the neck and upper torso of a human. [Figure 4B] An exemplary embodiment shows a ventral view of a representative catheter equipped with a positioning element (e.g., an anchor, adhesive, expandable coil / winding wire), the catheter having a window that can be positioned to align with nerve stimulation electrodes within the catheter, the representative catheter being inserted into the neck and upper torso of a human. [Figure 5] A perspective view of a typical catheter according to an exemplary embodiment is shown, comprising a conductor and electrodes, which are exposed to the outside of the catheter and include a fluid transport lumen. [Figure 6] A typical stimulating catheter, equipped with flexible electrical leads, a circuit, and electrodes, is shown. [Figure 7] The diagram shows the structure of selected nerves and blood vessels in the human neck and upper torso, along with a typical implantable stimulator (e.g., a catheter and pulse generator), control buttons, and a control device connected via wireless connectivity, according to an exemplary embodiment. [Figure 8] An exemplary embodiment shows the structure of the respiratory muscles of the torso, a transcutaneous respiratory muscle stimulation array with electrodes placed on the patient's skin over the intercostal muscles, a transesophageal stimulation electrode, and an external respiratory support device. [Figure 9] A block diagram of a nerve stimulation system having an intravascular catheter and a control device, according to an exemplary embodiment, is shown. [Modes for carrying out the invention]

[0049] The following description will provide specific details for the understanding of those skilled in the art. The examples of the Art described below are not exhaustive and do not limit the System to the same manner as any exemplary embodiment. Accordingly, the following description and drawings are illustrative and not restrictive.

[0050] Further aspects of the features of the present disclosure and exemplary embodiments are shown in the accompanying drawings and / or described in the text of this specification and / or in the accompanying claims. Both the above general description and the following detailed description are illustrative and descriptive only and do not limit the scope of the invention as described in the claims. As used herein, the terms “comprises,” “comprising,” “containing,” “having,” or other variations thereof are used to mean non-exclusive inclusion, so that an apparatus containing a list of processes, methods, articles or elements does not contain only those elements, but may also contain other elements that are not explicitly listed or are not specific to the above processes, methods, articles or apparatus. Furthermore, the term “representative” is used herein to mean “exemplary” rather than “ideal.” As used herein, the terms “about,” “substantially,” and “approximately” indicate a range of + / - 15% of the indicated value.

[0051] Next, the examples of the present disclosure described above will be explained in detail, as shown in the attached drawings. Throughout these drawings, the same or similar parts will be referred to using the same reference numerals wherever possible.

[0052] The terms “proximal” and “distal” are used herein to refer to the relative positions of typical components of a medical device or implant. As used herein, “proximal” refers to a position relatively close to the outside of the body or close to the operator using the medical device or implant. “Distal” refers to a position relatively far from the operator using the medical device or implant or close to the inside of the body.

[0053] In principle, embodiments of this disclosure relate to systems, medical devices, and methods for electrically stimulating a patient's nerves and preventing, regulating, controlling, or treating damage (e.g., damage to the brain, lungs, or diaphragm muscles). Damage may be caused or amplified by artificial respiration, for example. As used herein, the term “damage” may refer to a change in the integrity, activity, level, robustness, or state of a cell or molecule, or any other change that can be traced back to an event. For example, brain damage may also be nerve damage resulting from stress (repeated stress), inflammation, oxidative stress, disease, pain, stroke, and / or physical injury (e.g., surgery or trauma).

[0054] The methods described herein may include stimulating one or more nerves (e.g., one or more phrenic nerves and / or one or more vagus nerves). For example, the methods may include stimulating one or more respiratory muscles (e.g., diaphragmatic muscles) or a portion thereof by stimulating one or more nerves (e.g., phrenic nerves). Stimulation of one or more phrenic nerves may play a role in preventing or treating brain injury (e.g., caused by mechanical ventilation). For example, in a patient on mechanical ventilation, stimulation of the phrenic nerves may regulate the diaphragmatic muscles to reduce the pressure and time required from the ventilation. Alternatively, stimulation of the phrenic nerves may also elicit a brain response to reduce the factors causing brain injury (e.g., inflammation). Stimulation of one or more vagus nerves may also elicit a brain response to reduce the factors causing brain injury (e.g., inflammation), and in some cases, the methods may include blocking one or more vagus nerves so that the vagus nerve(s) do not send abnormal signals to the brain (e.g., signals that induce brain inflammation). Abnormal signals may result from mechanical ventilation.

[0055] The method may further include monitoring, detecting, and / or testing one or more functions, activities, or other parameters of the brain; obtaining the results of the detection or testing; and analyzing these results to determine, for example, the effects of neural stimulation and / or ventilation on brain function and / or activity. Based on the test results and their analysis, parameters for neural stimulation (e.g., timing, duration, and profile (e.g., intensity)) may be created or modified, and neural stimulation may be initiated or modified based on these parameters. Typical tests of brain function include magnetic resonance imaging (MRI) (e.g., functional MRI), computed tomography (CAT) scans, positron emission tomography (PET) scans, magnetoencephalography (MEG) scans, any other imaging or scanning method, electroencephalography (EEG) tests, detection of cardiac and / or respiratory events, and / or measurement of blood pressure, intracranial pressure, cardiopulmonary pressure, cerebral oxygenation, and partial pressure of carbon dioxide in arterial blood (PaCO2). Cerebral oxygenation can be monitored in several ways, including via jugular vein saturation, near-infrared spectroscopy, and / or microdialysis catheter assessment. Testing of brain function may also include clinical examination of one or more body fluids (e.g., blood, urine, fluids surrounding the brain) or one or more tissues. Clinical examinations can detect concentrations of molecules (e.g., cytokines) indicating brain damage or dysfunction (e.g., inflammation). Testing of brain function may further include neurological examinations (e.g., assessment of motor or sensory skills (e.g., reflexes, eye movements, gait and balance tests)) and tissue biopsies. Testing may further include cognitive assessments (e.g., assessing mental state) by asking the patient to perform specific tasks and answer several questions (e.g., stating today's date or following written instructions).

[0056] Alternatively, the method may further include testing the state of stimulation of one or more nerves (e.g., the vagus nerve). In some cases, the method may include testing brain function and the state of stimulation of one or more nerves. Typical tests of the state of stimulation of nerves (e.g., the vagus nerve) include detection of skin potentials, responses related to heart rate variability, pupil diameter and control of blood flow to the eye, peripheral blood flow (e.g., measured with a laser Doppler flowmeter), heart rate and blood pressure variability analysis, Valsalva maneuver, metronome breathing, sustained grasping test, cold pressor test, facial cooling test, active and passive orthostatic stress tests, blood pressure response to mental arithmetic tests, pharmacological baroreflex tests, thermoregulatory sweat tests, quantitative axonal reflex sweat tests, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), electroencephalography (EEG) waveform evaluation, measurement of visual, auditory and somatosensory evoked potentials, changes in absolute vital sign values, and changes in pain thresholds. The tests may also include detecting chemical components in blood or other body fluids (e.g., the concentration and activity of proteins or other molecules, e.g., molecules associated with inflammation or pain). Chemical tests may include measuring the levels and / or concentrations of TNF-α, other cytokines, serotonin, gastrin, and / or norepinephrine.

[0057] Brain function and / or vagus nerve stimulation tests can be performed during or after artificial respiration, or at different stages of artificial respiration. For example, the test can be performed before, during, or after the inflation phase of artificial respiration. Alternatively, the test can be performed before, during, or after nerve stimulation. The state or activity of brain function and / or vagus nerve stimulation can be determined based on the test results. Alternatively, results from tests performed at different times can be compared to each other, or to a reference threshold or range (e.g., a threshold or range indicating normal brain function or other levels of brain function). In such cases, the state of brain function and / or vagus nerve stimulation can be determined based on the comparison.

[0058] For patients receiving or who have received neurostimulation therapy, the patient's brain function and / or vagus nerve stimulation status can be detected and compared to parameters representing normal brain and / or nerve function and / or state. If differences are measured, one or more parameters of the neurostimulation can be modified to adjust the neurostimulation therapy applied to the patient. Adjustments can be made continuously to provide the patient with optimal and individualized treatment (e.g., based on real-time monitoring of brain function and / or vagus nerve stimulation status).

[0059] In some cases, the method may further include administering one or more agents to the subject during the neurostimulation, regulation and / or mechanical ventilation procedures described herein. In embodiments, drug therapy may be determined based on the analysis of any of the tests described above. In some cases, one or more agents may be useful in reducing brain injury in relation to reduced extubation time. For example, one or more agents may include propofol and / or dexmedetomidine. In some cases, one or more agents may be able to affect smooth muscle tone and / or reduce tracheobronchial tone / tension. Such agents may also help reduce abnormal vagal signaling induced by pulmonary stretch receptors, which can cause brain injury.

[0060] The systems of this specification may include medical devices for carrying out the methods described herein. The medical devices may include components (e.g., a catheter comprising a tubular member and one or more electrode assemblies, a signal generator providing stimulating energy to the electrode assemblies, one or more sensors for detecting the patient's condition and adjusting the stimulating signal, and one or more control components enabling a user (e.g., a physician or patient) to adjust the parameters of nerve stimulation). Different embodiments of the components of various medical devices may be combined and used together in any reasonable configuration. Furthermore, individual features or elements of any described embodiment may be combined with or used in conjunction with individual features or elements of other embodiments. Various embodiments may be used further in situations different from the specific situations described herein. For example, the disclosed electrode structures may be combined with or used in conjunction with various development systems well known in the art for various diagnostic and / or therapeutic applications.

[0061] The systems and methods disclosed herein can help a patient obtain at least one of the following: preventing, regulating, controlling or treating brain injury; preventing, regulating, controlling or treating lung injury; moving the diaphragmatic muscles (e.g., by stimulating the phrenic nerve); or providing respiratory support or mechanical ventilation.

[0062] In some embodiments, the systems and methods of this specification can reduce and prevent brain injury (e.g., in patients receiving or who have received mechanical ventilation) via phrenic or diaphragmatic stimulation. Electrical stimulation of at least one phrenic nerve and / or hemidiaphragm during mechanical ventilation can provide effective O2 / CO2 gas exchange while reducing barotrauma (extension injury) and atelectasis (lung collapse injury) in the upper lung fields. Reducing lung injury can reduce stimulation, which can lead to a cascade of events associated with brain inflammation and cognitive impairment. Electrical stimulation of one or more phrenic nerves or diaphragmatic muscles can stabilize afferent signaling to the brain, leading to the mitigation of abnormal vagus signaling involved in brain cell death. Activation of the diaphragmatic muscle by stimulating the phrenic nerve or other nerves / muscles can provide improved or stable sensory input to brain receptors compared to that delivered during mechanical ventilation alone (e.g., thereby replacing the input normally received by the brain during brain-induced diaphragmatic activation, such as signaling from the phrenic, vagus nerve, or pulmonary stretch receptors, as an unspecified example). The duration of stimulation can vary, as biological structures may require slight changes. Stimulation (e.g., phrenic, vagus nerve, muscle, etc.) can be provided by transvascular (e.g., transvenous) catheters, cuff electrodes, implantable electrodes, percutaneous stimulators, or other preferred methods. For example, vagus nerve stimulation can be provided by an external nerve stimulator (e.g., a stimulator placed in a skin area adjacent to the vagus nerve). Alternatively, vagus nerve stimulation can be provided by an implantable nerve stimulator.

[0063] In some embodiments, the systems and methods of this specification can reduce brain damage via vagus nerve block coordinated with respiration delivered by a ventilator. Electrical stimulation can be used to prevent abnormal pain signals, for example, by using a kilohertz frequency nerve block via the vagus nerve, which can reduce Akt (protein kinase B) inactivation and help mitigate cell death. The kilohertz frequency electrical stimulation can be delivered via electrodes placed in or near the vagus nerve (e.g., including its branches) to temporarily block afferent signals (e.g., at 40 kHz or about 40 kHz, or in the range of 1 kHz to 100 kHz). The blockage signal can be designed to occur in sync with a specific stage of mechanically delivered respiration (e.g., inspiration) to minimize abnormal signaling. The blockage signal can be designed so that its intensity is adjusted by one or more characteristics of respiration delivered by the ventilator (e.g., pressure, flow, tidal volume). Vagus nerve block signals can be delivered via transcutaneous electrodes, minimally invasively placed electrodes, transvenous electrodes, subcutaneous electrodes, direct contact electrodes, or other suitable delivery carriers. The stimulus profile envelope of the block signal can be adjusted to minimize the passage of abnormal vagus nerve signals to the brain, for example, by pulmonary stretch pain receptors. In one embodiment, the system may include sensors that adjust the timing, duration, and profile of the nerve block signal to optimize the blockage of abnormal signals. Sensors or other inputs can be used to trigger the block signal. For example, in one embodiment, detection of respiration (e.g., from a ventilator) can be used to coordinate / synchronize stimulation of the phrenic nerve(s) and / or vagus nerve(s) with the ventilator. One such sensor includes a mechanical transducer (e.g., a microphone) placed in the patient's neck or throat that can detect "pink noise" in the throat or endotracheal tube whenever respiration occurs. Alternatively, in another embodiment, the transducer may be attached to an airflow circuit (for example, an inspiratory branch where the inspiratory phase of respiration can be detected), or inserted into or attached to a portion of the airflow circuit tube. This can be used in invasive or non-invasive ventilators.In yet another embodiment, a mechanical transducer on part of the airflow circuit (e.g., a strain gauge) can function as a stretch sensor attached to or wrapped around a tube (an inspiratory branch, or a tube connecting a Y-shaped portion to the endotracheal tube). Pressure changes associated with the respiratory cycle can be detected by the mechanical transducer and the stimulus can be synchronized.

[0064] In some embodiments, the methods and systems of this specification can reduce diaphragmatic injury, lung injury, and brain injury via phrenic stimulation, and can reduce vagus nerve block that coordinates with respiration delivered by the vagus muscle (MV). Stimulating at least one phrenic nerve can move the diaphragm, which can stabilize abnormal signals sent to the brain via afferent pathways, alleviate diaphragmatic atrophy, and reduce lung injury. Diaphragmatic activation may also include stimulating at least one vagus nerve to block its signals. In one embodiment, both the left and right phrenic and vagus nerves can be stimulated. These stimulation signals can be delivered by one or more devices. A single catheter placed via the left (internal cervical) IJ or (external cervical) EJ can stimulate the left vagus nerve, left phrenic nerve, and right phrenic nerve. In one embodiment, a group of electrodes for delivering a left vagus nerve block can be placed proximal to other groups of electrodes. In such embodiments, the block cannot prevent distal phrenic signals from reaching the diaphragmatic muscle. Treatment can also be achieved by two or more separate devices. For example, an intravenous catheter placed in the jugular vein (internal or external jugular) or subclavian vein can be used in combination with an external vagus nerve stimulator attached to a cervical collar, a skin-attached percutaneous device, or a set of electrodes placed percutaneously. Vagus nerve block can be timed to occur by respiratory supply from a ventilator or by delivery of phrenic nerve stimulation. Various sensors can be used to regulate the patient's respiration and / or respiratory supply and stimulation from a ventilator. Sensors can detect heart rate, CO2, O2, respiration, temperature, exercise, impedance, electromyography, electrocardiogram, airflow, pressure, or any combination thereof.

[0065] In some embodiments, the methods and systems of this specification can reduce diaphragmatic injury, lung injury, and / or brain injury via phrenic and / or vagal nerve stimulation, and in some cases can reduce vagal nerve block in coordination with respiration delivered by a ventilator. Electrical stimulation can also be used to deliver anti-inflammatory signals via the vagus nerve. Low duty cycle signaling may be effective in providing long-term cerebral protection. In one embodiment, a positive vagal pulse train can be delivered during phrenic stimulation pulses. Alternatively, a blocking pulse to the vagus nerve can be delivered during, simultaneously with, or partially overlapping with, positive stimulation pulses to the vagus nerve. For example, a positive (passivation) signal can be delivered to the brain via the vagus nerve during the time between respirations, and a vagal nerve block can be established when a ventilator extends the lungs to prevent pain signals from reaching the brain. The blocking signal can be designed so that its intensity is adjusted by one or more characteristics of the respiration delivered by the ventilator (e.g., pressure, flow, tidal volume, etc.). A positive signal to the vagus nerve can be designed so that its intensity is adjusted by one or more characteristics of the respiration delivered by the ventilator (e.g., inverse proportion to pressure, flow, tidal volume, etc.). In some cases, vagus nerve stimulation immediately after an ischemic event may also be neuroprotective. For example, a patient may receive a pulse train sent to the vagus nerve after a cerebral ischemic event. When the ventilator inflates the lungs, the pulse train can be interrupted to establish a nerve block, and thus the positive signal can be resumed between breaths. Alternatively, the positive signal can be sent continuously, and it can be interrupted by a high-frequency nerve block (e.g., every few seconds). In some cases, the positive signal does not need to be sent constantly or for long periods of time. For example, the positive signal can be sent once every few hours or once a day.

[0066] Vagus nerve stimulation may be transvascular, percutaneous, or via minimally invasive electrodes placed near the vagus nerve. The technique may selectively include activating and / or blocking efferent and afferent nerve pathways. This may include simultaneous afferent vagus block and efferent phrenic stimulation. Other embodiments include vagus nerve stimulators that deliver a nerve block during the inspiratory phase of mechanical ventilation and then an anti-inflammatory stimulating signal to the vagus nerve at other times (e.g., a ventilator that delivers a high-frequency block when stretch receptors are activated and an anti-inflammatory signal at other times, or a jugular vein catheter for vagus nerve stimulation synchronized with the phrenic nerve stimulation signal).

[0067] In some embodiments, the methods and systems of this specification can reduce brain injury through phrenic pacing in mechanically ventilated patients. Aspects of this disclosure may include systems and methods for reducing peak ventilator pressure, limiting end-expiratory lung extension to reduce pneumonia and provide adequate ventilation, and reducing atelectasis injury.

[0068] In some embodiments, the methods and systems described herein can reduce brain damage by reducing the positive pressure required from external respiratory support and by inhibiting the effects of abnormal vagal signaling. Multiple means can be used to reduce positive pressure, including iron lungs, extracorporeal membrane oxygenation (ECMO), and phrenic nerve and respiratory muscle (e.g., diaphragm, intercostal, etc.) stimulation. Abnormal vagal signaling can also be mitigated by any means used to reduce the activation of pulmonary stretch receptors, as well as by using vagal / phrenic stimulation or nerve blocks.

[0069] Figure 1 shows the structures of the neck and thoracic region, in particular the relative positions of the left and right phrenic nerves (PhN), vagus nerve (VN), internal jugular vein (IN), brachiocephalic vein (BCV), subclavian vein (SCV), and superior vena cava (SVC). The PhN extends nearly perpendicularly to and adjacent to the BCV in regions 107R and 107L, near the IN / BCV junction. Each PhN can have two or more branches. The branches can join at variable positions ranging from the cervical region to the thoracic region below the IN / BCV junction. In the latter case, a branch of the PhN on one side of the body can proceed to the opposite side of the BCV. The right PhN may include a branch that proceeds to one side of the SVC. The left and right PhNs extend to the left and right hemidiaphragms (HDs), respectively. Leaving the medulla oblongata, the vagus nerve (VN) extends downwards into the neck between the trachea and esophagus, into the chest and abdomen, and further forms an extensive information network with various organs (e.g., lungs, diaphragm, etc.) and other tissues. The right vagus nerve gives rise to the recurrent laryngeal nerve, which descends into the neck between the trachea and esophagus.

[0070] Referring to Figure 2, the system described herein may include several components, including: a stimulator having one or more electrodes or electrode assemblies (e.g., a transvascular nerve stimulation catheter 12 including stimulating electrodes (e.g., shown in Figure 2), or a percutaneous stimulation array 13 (Figure 8)); a signal generator 14 that provides stimulation energy to the electrode assemblies; one or more sensors 16 or means for sensing the patient's condition and informing adjustments to the stimulation signal and / or external respiratory support; and a control device 18 that manages parameters associated with the delivery of stimulation signals to the electrodes. In some embodiments, the system may incorporate a remote controller 20, a graphical user interface (GUI) 21, a touchscreen (e.g., as part of the GUI 21), a handheld controller (e.g., the remote controller 20), a keyboard, a computer (e.g., the control device 18), a smartphone, a tablet, or other input device.

[0071] In some cases, the stimulator (e.g., catheter 12) is easily applied to or inserted into the patient, is temporary, and can be easily removed from the patient later without requiring surgery. The stimulator (e.g., catheter 12 or other stimulator array) can be placed inside the patient through a percutaneous incision in the patient's neck. In some cases, the stimulator may be inserted close to the subclavian, femoral, or radial region of the patient. In other cases, as described herein, the stimulator can be placed outside the patient.

[0072] The various system components described herein can be combined and used together in any reasonable configuration. Furthermore, individual features or elements of any example described herein may be combined with or used in conjunction with individual features or elements of other embodiments. Various examples may be used further in situations different from the specific situations described herein. For example, the disclosed electrode structures may be combined with or used in conjunction with various development systems well known in the art for various diagnostic and / or therapeutic applications.

[0073] Figure 2 shows the structures of the neck and thoracic region, and in particular the relative positions of the left and right phrenic nerves (L.PhN28 and RPhN28), vagus nerves (L.VN7 and R.VN9), left and right internal jugular veins (L.IJV32 and R.IJV33), left and right brachiocephalic veins (L.BCV25 and R.BCV27), left and right subclavian veins (L.SCV22 and R.SCV23), superior vena cava (SVC24), and intercostal nerves (IN29). Figure 2 further shows the diaphragm 30 and intercostal muscles 39. The phrenic nerves 26 and 28 extend nearly perpendicularly to and adjacent to the subclavian veins 22 and 23, or in some cases, nearly perpendicularly to and adjacent to the brachiocephalic veins 25 and 27 near the junction between the internal jugular veins 32 and 33 and the brachiocephalic veins 25 and 27. Each phrenic nerve 26, 28 may have two or more branches. The branches can join at variable locations in the thoracic region, ranging from the cervical region to the junction between the internal jugular veins 32, 33 and the brachiocephalic veins 25, 27. In the latter case, the branches of the phrenic nerves 26, 28 on one side of the body may proceed to the opposite side of the brachiocephalic veins 25, 27. The right phrenic nerve 28 may include a branch that proceeds to one side of the superior vena cava 24. The left and right phrenic nerves 26, 28 extend to the left and right hemidiaphragms, respectively.

[0074] Figure 2 also shows a medical system 100 including a transvascular nerve stimulation catheter 12 and a control device 18. The catheter 12 may include a plurality of electrodes 34. The catheter 12 can be operably connected to the control device 18 (e.g., wired, wireless, etc., via cable 5). The control device 18 can be programmed to perform any of the functions described herein in relation to the system 100. In some embodiments, the control device 18 may include a remote controller 20 that allows a patient or healthcare professional to control the operation of the control device 18 from a distance. The remote controller 20 may include a portable terminal as shown in Figure 2. In some examples, the remote controller 20 may include a hand switch, a foot switch / pedal, a voice-activated, touch-activated or pressure-activated switch, a remote switch, or any other form of remote actuator. The control device 18 may include a touchscreen, which may be supported by a cart 41.

[0075] The remote controller 20 may include buttons 17, 19 that can be pressed by the patient or other users to control the breathing pattern. For example, pressing one of the buttons 17, 19 can initiate “expiratory” breathing, thereby allowing more air than the previous breath to enter the patient’s lungs. Expiratory breathing can occur when the electrodes 34 of the catheter 12 are instructed to stimulate one or more of the phrenic nerves 26, 28 at a level higher than normal breathing (e.g., by prolonged stimulation or by a stimulation train with pulses having higher amplitude, pulse width, or frequency). High-amplitude stimulation pulses can recruit additional nerve fibers, thereby engaging additional muscle fibers to produce stronger and / or deeper muscle contractions. Extended pulse width or duration of the stimulation train can deliver stimulation over a longer period, extending the duration of muscle contraction. When stimulating the diaphragmatic muscle, long pulse width or duration of stimulation (a train of pulses) may help expand the lower lobes by applying a large or widespread negative pressure around the outside of the lung. Such negative pressure may help prevent or mitigate a form of low-pressure lung injury known as atelectasis. Increasing the stimulation frequency can result in a stronger contraction of the diaphragm 30. Increased stimulation of one or more phrenic nerves 26, 28 (e.g., higher amplitude, pulse width, stimulation duration, or frequency) can result in a stronger contraction of the diaphragm 30, causing the patient to inhale a larger volume of air, thereby providing the patient with a larger volume of oxygen. Expiratory breathing can increase the patient's comfort.

[0076] In other examples, buttons 17 and 19 allow the patient or other user to start and stop stimulation therapy, or to increase or decrease stimulation parameters, including the amount of stimulation per session (amplitude × pulse width), the number of pulses in a stimulation sequence, or respiratory rate. LED indicators or small LCD screens (not shown) on the remote controller 20 or control unit 18 can provide the operator with other information regarding stimulation parameters, feedback from system sensors, or the patient's condition.

[0077] Alternatively, a control device having the functions of control device 18 can be implanted in the patient together with the catheter 12, as shown in Figure 7. In this example, the remote controller and programmer can communicate wirelessly with the implanted control device. Each programmer, implanted control device, and remote controller may include a wireless transceiver, so that each of the three components can communicate wirelessly with the others. The implanted control device may include all the electronics, software, and functional logic necessary to perform the functions described herein. Implantation of the control device enables the catheter 12 to function as a permanent respiratory pacemaker. The programmer can enable the patient or healthcare professional to modify or program nerve stimulation or sensing parameters. In some examples, the remote controller 20 can be used as described in relation to Figures 2, 3, and 8. In other examples, the remote controller 20 may be in the form of a smartphone, tablet, wristwatch, or other suitable input device.

[0078] In yet another additional or alternative example, the control device of system 100 may be portable. The portable control device may include all the functions of the control device 18 in Figure 2, but it may be carried by the patient or other user, providing greater mobility to the patient, and may be detached from the cart 41. In addition to carrying the portable control device, the patient may wear the control device, for example, on a belt, on other clothing, or around his / her neck. In another example, the portable control device may be placed on the patient's bed to minimize the footprint of system 100 in the area around the patient, or it may provide mobile muscle stimulation in situations where a bedridden patient needs to be transported or moved to another location.

[0079] The distal tip of catheter 12 may be the tapered distal end of catheter 12 and may have a smaller circumference than the body of catheter 12. The distal tip may be open at the distal end to allow a guidewire to advance distally through and beyond catheter 12. The distal tip may be softer than the rest of catheter 12, may be non-invasive, and may have a rounded edge. Catheter 12 may also have one or more ports or openings in the side wall of the catheter. A first opening may be located in the middle of catheter 12, and other openings may be located near the proximal end of catheter 12. Each opening can be in fluid communication with the corresponding lumen of catheter 12, through which fluid can be injected or extracted. Fluid can exit and / or enter through the ports to enter and / or be delivered into and / or from blood vessels.

[0080] During use, the proximal end of the catheter 12 can be placed in the left subclavian vein 22, and the distal end of the catheter 12 can be placed in the superior vena cava 24. In this configuration, the electrode 34 at the proximal end of the catheter 12 may be positioned close to the left phrenic nerve 26, and the electrode 34 at the distal end of the catheter 12 may be positioned close to the right phrenic nerve 28. As for other insertion sites, the catheter 12 can be inserted into the jugular vein (e.g., the left jugular vein 32 (e.g., the left external jugular vein or the left internal jugular vein) or the right jugular vein 33 (e.g., the right external jugular vein or the right internal jugular vein)) and the superior vena cava 24, with the proximal electrode positioned to stimulate the left phrenic nerve 28 and the distal electrode positioned to stimulate the right phrenic nerve 28.

[0081] The left and right phrenic nerves 28, 28 can supply nerves to the diaphragm 30. Therefore, the catheter 12 can be positioned to electrically stimulate one or both of the left and right phrenic nerves 26, 28 to induce contraction of the diaphragmatic muscle 30 (or a part thereof), thereby initiating or assisting the patient's breathing, helping to reduce pressure from the ventilator, expanding the lower lung, reducing lung stretch / injury, and / or reducing abnormal brain signaling that may lead to cognitive impairment.

[0082] In further examples, the catheter 12 can be placed in and advanced within other blood vessels (e.g., jugular vein, axillary vein, cephalic vein, peripericardial vein, brachial vein, or radial vein) that provide access to a location adjacent to the target nerve(s) (e.g., the phrenic nerve). Furthermore, the stimulator (e.g., catheter 12 or array 13) can activate the target nerve using other forms of stimulating energy (e.g., ultrasound). In some examples, the system 100 can also target other respiratory muscles (e.g., intercostal muscles) in addition to or instead of the diaphragm 30. Energy can be delivered via one or more types of electrodes / methods, including percutaneous electrodes, subcutaneous electrodes, electrodes configured to be positioned in contact with the nerve (e.g., nerve cuffs), percutaneous electrodes / stimulation, or other techniques known in the art.

[0083] The neurostimulation systems and methods described herein can reduce or eliminate the need for a patient to receive external respiratory support. The external respiratory support 88 in Figure 2 may include any device or method for correcting or enhancing blood gases and / or helping to reduce the patient's respiratory work. Some non-limiting examples include mechanical ventilation, non-invasive ventilation (NIV), CPAP, BiPAP, nasal oxygen cannula, DPS (Synapse, Avery, etc.), and ECMO, as described below.

[0084] Mechanical ventilation can refer to the use of a ventilator to assist or replace spontaneous breathing. Mechanical ventilation is called "invasive" if it involves any device that penetrates through the mouth (e.g., an endotracheal tube) or skin (e.g., a tracheostomy tube). There are two main types of mechanical ventilation: positive pressure ventilation (introducing air (or another gas mixture) into the trachea via positive pressure) and negative pressure ventilation (bringing air into the lungs (e.g., an iron lung) (e.g., inhaling)). There are many modes of mechanical ventilation. Mechanical ventilation may be necessary when a patient's spontaneous breathing cannot provide effective gas exchange in the lungs.

[0085] Mechanical ventilation can also be provided via a laryngeal mask airway (e.g., a laryngeal mask), which is designed to keep the patient's airway open while they are under anesthesia or unconscious. It is often referred to as a type of supraglottic airway. A laryngeal mask may include an airway tube that connects to an oval mask with a cuff, which is inserted into the trachea through the patient's mouth. Once in place, the device can provide a safe or stable airway by forming an airtight seal above the glottis (unlike an endotracheal tube that passes through the glottis).

[0086] Non-invasive ventilation (NIV) is the use of airway management administered through a face (e.g., oral, nasal, or naso-oral) mask / cannula instead of an endotracheal tube. Inhaled gas is obtained by positive end-expiratory pressure, often by pressure support, or by an assisted-controlled ventilator at a set tidal volume and rate. This type of treatment is called "non-invasive" because it is delivered through a mask or other means attached to the face or nose but without requiring endotracheal intubation. Other forms of non-invasive ventilation include the use of an external negative pressure system, such as those used in iron lungs. Any device used to reduce pressure outside the patient's thoracic cavity or torso can also effectively provide NIV.

[0087] Continuous positive airway pressure (CPAP) is a form of positive airway pressure ventilation that continuously keeps the airways open by applying a constant, moderate amount of air pressure. CPAP can be used for patients who are capable of breathing spontaneously on their own but may require a certain level of pressure support. It is a variation of positive end-expiratory pressure (PEEP). Both therapies help stents open the alveoli in the lungs, thus replenishing a large portion of the lung surface area for ventilation. "PEEP" generally refers to a device that applies positive pressure only at the end of exhalation. A CPAP device applies continuous positive airway pressure throughout the entire respiratory cycle. Therefore, ventilation itself does not circulate during CPAP, no additional pressure above the CPAP level is applied, and the patient must initiate each breath on their own.

[0088] Bilevel positive airway pressure (BiPAP) therapy is very similar to CPAP in terms of function and design. BiPAP can also be configured to include a respiratory timing function that measures the amount of air a person should breathe per minute. If the time between breaths exceeds a set limit, the ventilator can force the person to breathe by temporarily increasing the air pressure. The main difference between BiPAP and CPAP devices is that BiPAP machines typically have two pressure settings: a set pressure for inhalation (ipap) and a lower pressure for exhalation (epap). The dual settings allow the patient to move more air in and out of their lungs.

[0089] Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal cardiopulmonary support (ECLS), is an extracorporeal technology that provides long-term cardiac and respiratory support to patients whose hearts and lungs are unable to obtain sufficient gas exchange. The technology of ECMO is similar to that used during cardiopulmonary bypass, and it is typically used to provide short-term support. During ECMO, blood is drawn from the human body and passes through the device, where carbon dioxide is removed and oxygen is delivered to the red blood cells. Long-term ECMO patients may often exhibit respiratory muscle weakness due to muscle inactivity and other causes. Certain therapeutic methods described herein may include delivering stimulation therapy to patients receiving ECMO and other forms of external respiratory support. Certain therapeutic methods of this disclosure can be carried out using an ECMO device containing a stimulation array.

[0090] In some cases, the catheter 12 can be inserted into (and / or fixed to) the patient. In many embodiments, the catheter 12 can be removed from the patient's body as needed without requiring surgery. For example, the catheter 12 in Figure 3 can be withdrawn once the patient breathes on their own.

[0091] The timing of stimulation of one or more nerves may be coordinated with the timing of mechanical ventilation. For example, a nerve (e.g., the vagus nerve) can be stimulated during at least a portion of the inspiratory period of mechanical ventilation.

[0092] Alternatively, the timing of stimulation of multiple nerves may also be coordinated. For example, a first nerve may not be stimulated by one or more electrodes of the first set of electrodes of the catheter, while a second nerve is stimulated. In some cases, when a nerve is not stimulated (e.g., when the nerve is blocked or no stimulation is provided), stimulation of one or more parts of the respiratory muscles (e.g., the diaphragm) may be performed. In some cases, the output from one or more nerve stimulating electrodes may occur inversely correlated with the output from two or more diaphragm stimulating electrodes. Alternatively, the output from one or more nerve stimulating electrodes may occur between the output from two or more diaphragm stimulating electrodes.

[0093] Figure 3 shows a typical medical system 300 including two catheters (12 and 62), each catheter containing one or more lumens and comprising electrode assemblies (34 and 64) including a proximal electrode assembly and a distal electrode assembly. The proximal and distal electrode assemblies of each catheter may each contain at least one or more electrode sets. The electrode assemblies 34 and 64 can be placed on or within the tubular member or catheter body of catheter 12 or 62. Catheters 12 and 62 can be placed in a patient through the patient's external or internal jugular vein, brachiocephalic vein, superior vena cava, brachial vein (not shown), radial vein (not shown), and / or left subclavian vein. Catheters 12 and 62 can be positioned such that at least one of the electrode sets faces the phrenic nerve and at least one of the electrode sets faces the vagus nerve. For example, catheters 12 and 62 can be positioned such that at least one electrode set points toward the left phrenic nerve, at least one electrode set points laterally toward the right phrenic nerve, and at least one electrode set points toward the vagus nerve. Thus, once positioned, the catheters can receive signals from the control device 14 and use the electrodes or electrode sets to stimulate one or both of the left phrenic nerve and / or the right phrenic nerve and / or the vagus nerve. As shown in Figure 3, catheter 12 can be configured to stimulate the left and right vagus nerves, and catheter 62 can be configured to stimulate the right vagus nerve and the right phrenic nerve. The catheter may further include a manifold 36 that extends outside the patient. Electrical cables and a pigtail lumen can extend from the manifold 36. At least one electrical cable 5 or 6 and the pigtail lumen may include a cable connector that connects to an external element, and the electrical cable can be connected to the electrical control device 14 via the cable connector. The electrical cable may be formed from lead wires that connect to the electrode assembly. Cable connectors can be attached to cables (e.g., by soldering, crimping, PCB, etc.), and one or both of the cable connectors may include threading.Alternatively, one or both of the cable connectors may include push-pull compression fittings or slip-lock fittings (not shown). The control device 14 and other elements may be electronically connected to components within the catheters 12, 62 for both transmitting and receiving signals and / or data in order to selectively stimulate the electrode set and / or monitor the patient and any response to the stimulation. Alternatively, the cables may include one or more luminal or fluid lines connected to one or more lumens of the catheters 12, 82. Furthermore, the system may include a push button 17 which can trigger stimulation or detection or any other function of the control device 14.

[0094] As shown in Figure 4A, the subclavian catheter 12 may include two axially extending groups (72a and 72b) of the proximal foramen or window. Each axially extending group includes a window. The electrodes and corresponding windows may be of any shape (e.g., circular, oval, crescent, elliptical, rectangular, etc.). In one embodiment, most of the windows within each group are located within the same 180-degree circumferential position around the outside of the catheter, thereby allowing the 180-degree circumferential position to differ between the first electrode group and the second electrode group (e.g., having different axial positions along the outside of the catheter). In another embodiment, the two groups of windows 72a and 72b may be substantially aligned longitudinally (e.g., within the same 90-degree circumferential position), where the 90-degree circumferential positions of the first and second groups are different but may overlap. For example, as shown in Figure 4A, one proximal window in the first row 72a is at a different circumferential position around the outside of the catheter, but is located at the same axial position as the window in the second row 72b. When placed in a patient, the two rows 72a and 72b of the proximal window may be substantially posteriorly oriented, and at least one proximal window may be oriented towards, adjacent to, or near the left phrenic nerve. The catheter may also include two axially extending rows (74a and 74b) of the distal foramen or window. Each axially extending row (74a, 74b) also includes distal windows located at different axial positions along the outside of the catheter, but at the same circumferential position around the outside of the catheter. The two rows 74a and 74b of the distal window do not have to be aligned, such that one distal window in the first row is axially between the two distal windows of the second row. For example, as shown in Figure 4A, one distal window in the first row 74a is located at a different axial position, and the window in the second row 74b is located at a different circumferential position around the outer edge of the catheter. When placed in a patient, the two rows 74a and 74b of the distal windows may be substantially oriented laterally (towards the right side of the patient), and at least one distal window may be oriented toward, adjacent to, or near the right phrenic nerve.In the example shown in Figure 4A, when viewed ventrally, the two misaligned rows of the three distal windows (74a, 74b) can appear as one row of the six distal windows, since one row faces anteriorly and the other faces posteriorly.

[0095] As shown in Figure 4A, a separate jugular vein catheter 62 can be inserted into the left or right jugular vein. The jugular vein catheter may include a group of openings or windows 66, so that when placed in a patient, at least one window can be directed toward, adjacent to, or near the vagus nerve.

[0096] A window on the catheter may include a vascular lumen into which the catheter is inserted, exposing electrodes and allowing a conductive path between the electrode set or electrode pair and the surrounding tissue. Alternatively, electrodes may be printed onto the surface of the catheter by one of several known means (e.g., conductive ink, polymer, etc.). Furthermore, electrodes may be integrated within a flexible printed circuit board, which may be attached to or incorporated into the catheter. Insulation means known in the art are used to ensure that electrodes are not exposed for direct contact with the patient and that no unnecessary electrical elements are exposed for that purpose.

[0097] Figure 4B shows a catheter 12 placed in the superior vena cava through the jugular vein. The catheter 12 may include rows of openings or windows 86 located proximal, mid, and distal, so that when the catheter 12 is placed in a patient, at least one window may be positioned facing, adjacent to, or near the left phrenic nerve, at least one window may be positioned facing, adjacent to, or near the right phrenic nerve, and / or at least one window may be positioned facing, adjacent to, or near the vagus nerve. The windows 86 on the catheter may include vascular lumen into which the catheter is inserted, exposing electrodes and allowing a conductive path between the electrode set or electrode pair and the surrounding tissue. The catheter 12 may include features to fix or stabilize the catheter and / or electrodes at a designated location within the patient. In one embodiment, the catheter 12 may have a helical shape at the distal end, the proximal end, or both. This shape can be formed by heat-treating a polymer sheath or tube, or by adding a molded stainless steel wire or shape-memory nitinol wire or any other shape-memory alloy. The shape-memory alloy can activate its helical shape when heated to a temperature of 30°C to 45°C (e.g., 37°C). This helical shape can help to align with the blood vessel wall, thus helping to position the catheter in its current location. The helical shape can also increase the radial electrode coverage area of ​​the blood vessel. This single catheter can be used to stimulate the phrenic nerve (PN) and / or vagus nerve (VN).

[0098] In one example shown in Figure 4B, the distal or proximal end of the catheter 12 may be configured to exhibit a helical shape when placed in the patient to help fix the catheter 12 to the blood vessel wall or to stabilize the catheter 12 during nerve stimulation. The helical shape allows electrodes 34 to be positioned at different radial positions within the vessel and relative to the target nerve. Selecting electrodes 34 at different radial positions within the vessel (whether or not due to the arbitrary helical shape) or at different distances from the target nerve (whether or not due to the arbitrary helical shape) may be useful for nerve stimulation. For example, in certain cases it may be desirable to stimulate the nerve with an electrode 34 closer to the nerve (e.g., to obtain a strong respiratory muscle response), while in other cases it may be desirable to stimulate the nerve with an electrode 34 further away from the nerve (e.g., to obtain a weak respiratory muscle response or to prevent unnecessary nerve stimulation).

[0099] Referring to Figure 5, the catheter 12 may include a stimulation array comprising a plurality of electrodes 34 or other energy delivery elements. In one example, the electrodes 34 may be surface electrodes located on the outer wall of the catheter 12. In another example, the electrodes 34 may be positioned radially inward relative to the outer wall of the catheter 12 (e.g., exposed through an opening or window in the outer wall). In yet another example, the electrodes 34 may include printed electrodes, as described in U.S. Patent No. 9,242,088, which are incorporated herein by reference.

[0100] The electrodes 34 can partially extend around the catheter 12. This “partial” electrode configuration allows the electrodes 34 to target the desired nerve for stimulation while minimizing the application of charge to undesirable areas of the patient’s anatomical structure (e.g., other nerves or the heart). As shown in Figure 5, the catheter 12 may include a proximal set 35 of electrodes 34 positioned near the left phrenic nerve 26 and configured to stimulate it, and a distal set 37 of electrodes 34 positioned near the right phrenic nerve 28 and configured to stimulate it. The electrodes 34 can be arranged in groups extending along the length of the catheter 12. For example, the proximal set 35 may include two rows of electrodes 34 extending parallel to the longitudinal axis of the catheter 12, and the distal set 37 may include two rows of electrodes 34 extending parallel to the longitudinal axis of the catheter 12.

[0101] Furthermore, the catheters described herein are subject to U.S. Patent No. 8,571,662 (issued October 29, 2013, titled "Transvascuiar Nerve Stimulation Apparatus and Methods"), U.S. Patent No. 9,242,088 (issued January 26, 2016, titled "Apparatus and Methods for Assisted Breathing by Transvascuiar Nerve Stimulation"), U.S. Patent No. 9,333,363 (issued May 10, 2016, titled "Systems and Related Methods for Optimization of Multi-Electrode Nerve Pacing"), U.S. Patent Application No. 14 / 383,285 (filed September 5, 2014, titled "Transvascuiar Nerve Stimulation Apparatus and Methods"), and U.S. Patent Application No. 14 / 410,022 (filed December 19, 2014, titled "Transvascuiar Nerve Stimulation Apparatus and Methods"). Any features of nerve stimulators and detectors described in the documents “Diaphragm Pacing Systems and Methods of Use” (U.S. Patent Application No. 15 / 606,867, filed May 26, 2017, titled “Apparatus And Methods For Assisted Breathing By Transvascuiar Nerve Stimulation”) or U.S. Patent Application No. 15 / 666,989, filed August 2, 2017, titled “Systems And Methods For Intravascular Catheter Positioning and / or Nerve Stimulation”) may be included, and the whole thereof is incorporated herein by reference. Furthermore, the control devices described herein may have any of the functions of the control devices described in the aforementioned patent documents (for example, the control devices described herein may carry out the nerve stimulation methods described in the incorporated documents).

[0102] During nerve stimulation, one or more electrodes 34 can be selected from the proximal set 35 for stimulating the left phrenic nerve 26, and one or more electrodes 34 can be selected from the distal set 37 for stimulating the right phrenic nerve 28. The catheter 12 can stimulate the nerves using a combination of monopolar, bipolar, or tripolar electrodes, or any other suitable combination of electrodes 34. In some examples, a second or third group of electrodes can be used to stimulate other respiratory muscles. Generally, a stimulator or stimulator array can include multiple sets of electrodes, where each set is configured to stimulate the same or different nerves or muscles. When multiple nerves or muscles are stimulated, the controllers and sensors described herein can be used to coordinate the stimulation to obtain a desired level of muscle activation, respiration, or respiratory assistance.

[0103] As shown in Figure 5, the catheter 12 may further include one or more lumens. Each lumen may extend from the proximal end of the catheter 12 to the distal end of the catheter 12, or to a position adjacent to the distal end of the catheter 12. In some examples, lumens may include sensors (e.g., blood gas sensors, electrical sensors, motion sensors, flow sensors, or pressure sensors) or may be in fluid communication with them. In some examples, the catheter 12 may include three lumens (not shown) that can be connected to dilating lumens 38, 40, 42 extending proximal from the hub 36. Any lumen within the catheter 12 may terminate at one or more distal ports 52, 50, 48 at the distal end of the catheter 12, or on the side wall of the catheter 12. In one example, lumens may be used to transport fluids to and from a patient (e.g., to deliver drugs, or to extract blood or other body fluids, remove CO2, inject oxygen, etc.). In other examples, these lumens can be used to hold guidewires, reinforcing wires, fiber optic cameras, sensors, or other medical devices. For example, Figure 5 shows a fiber optic camera 46 embedded in a lumen 38, extending through the corresponding lumen and exiting through a distal port 48. Electrodes 34 can be configured to detect physiological information from the patient (e.g., blood properties, nerve activity, ECG, or electrical impedance).

[0104] The catheter 12 or other stimulators of the present disclosure may incorporate external markers or other indicators to help guide the positioning and orientation of the device. The catheter 12 or other stimulators of the present disclosure may also include visible internal indicators (e.g., radiopaque markers, contrast agents such as barium sulfate, echogenicity markers, etc.) by X-ray, ultrasound, or other imaging techniques to help position the stimulator in the desired location. The catheter 12 may include any combination of the features described herein. Therefore, the features of the catheter 12 are not limited to the specific combination shown in Figure 5.

[0105] Furthermore, relating to Figure 5, the hub 36 can be connected to the proximal end of the catheter 12. The hub 36 may include a conductive surface, which can act as a reference electrode during unipolar stimulation or detection. In some embodiments, the hub 36 can be sutured to the patient's skin. Furthermore, the hub 36 can be used as an ECG or other reference electrode.

[0106] The embodiment shown in Figure 5 includes a catheter 12 having 20 proximal windows 35 (two rows of 10 windows) and 8 distal windows 37 (two rows of 4 windows). However, in other embodiments, the catheter may have fewer or more rows and varying numbers of proximal or distal windows. For example, in other embodiments, the catheter may include 2, 4, 8, 10, or 12 or more proximal windows arranged in one, two, or three or more rows, and / or 2, 4, 6, 10, or 12 or more distal windows arranged in one, two, or three or more rows. The number of windows may be odd. The windows may be formed by excising the outer wall of the catheter 12 (e.g., by laser, manual cutting, perforation, punching, etc.), or the windows may be formed by extrusion, 3D printing, or any other suitable method in any other manufacturing process. The windows may be rectangular, elliptical, square, or other shapes. The windows may be holes configured to allow electrical signals to move from the lumen of the catheter to the outside of the catheter. Each window may include electrodes that are exposed through the window and electrically connected independently to other electrodes to the control device. U.S. Patent Application No. 15 / 606,867 (incorporated by reference) describes such connections. In further or alternative embodiments, the windows may be covered with a material that allows the passage of electrical signals.

[0107] The dimensions of the catheter 12 can be customized to suit the anatomical structure of a particular patient (e.g., different sizes for humans, pigs, chimpanzees, etc.). However, in some embodiments, the length of the portion of the catheter including the proximal window may be 16 cm or less, between 3 cm and 5 cm, or between 1 cm and 3 cm. The length of the portion of the catheter including the distal window may be 12 cm or less, between 2 cm and 4 cm, or between 1 cm and 2 cm. The distance between two adjacent windows (whether the windows are adjacent circumferentially in the same row of windows or longitudinally) may be 5 cm or less, 3 cm or less, about 1 cm, or less than 1 cm. The dimensions of the catheter are illustrative only, and the catheter may have dimensions different from the above range and specific actual dimensions. Furthermore, the catheter 12 may include windows with configurations different from those described above.

[0108] The distal tip of the catheter may be the tapered distal end of the catheter 12. The distal tip may be open at the distal end to allow the guidewire to pass through and beyond the catheter distally. The distal tip may have a smaller circumference than the body of the catheter, and it may be softer than the rest of the catheter, non-invasive, and have a rounded edge.

[0109] The catheter may also have ports 38a, 40a, and 42a that are connected proximally to the individual tubes 48, 50, and 52, and can act as one or more separate vascular lines (three, as shown in Figure 5) to help inject different fluids.

[0110] Figure 6 shows another example of the catheter 12. The catheter 12 shown in Figure 6 is similar to the catheter in Figure 5, except for the electrode 34, and it can be formed by conductive ink (e.g., silver, gold, graphene, or carbon flakes suspended in a polymer or other medium) printed on the surface of the catheter 12, as described in U.S. Patent No. 9,242,088 (incorporated herein by reference). These conductive inks may be placed and adhered directly onto the catheter 12 and sealed by an outer polyurethane or other flexible and insulating film / material, except for the exposed electrode 34. The electrode may be in the form of a lead wire, a flexible solid-state circuit attached to or incorporated in or on the catheter or another surface. The exposed electrode 34 may be coated (e.g., coated with titanium nitride) for several purposes, such as improving electrical properties (e.g., conductivity and surface area), providing corrosion resistance, or reducing the possibility of toxic silver oxide formation. As shown in Figure 6, the conductive ink trace of the distal electrode can advance proximal along the catheter 12, beyond the more proximal electrode 34. Figure 6 further shows the catheter 12 with an ultrasonic transducer 54 or other sensor at its distal end.

[0111] Figure 7 shows an alternative medical system having elements similar to the medical system in Figure 2. This medical system includes wireless connections from a control unit 14' to the catheter 12, and wireless connections from a push button(s) to the wireless control unit 14'. In this alternative system 10, the control unit 14' is implanted in the patient together with the catheter 12. System 10 may further include a remote controller 18 and a programmer 98 that wirelessly connect to the control unit 14'. In this embodiment, each of the programmer 98, the control unit 14', and the remote controller 18 may include wireless transceivers 92, 94, and 96, respectively, so that each of the three components can wirelessly connect to one another. The control unit 14' may include all the electronics, software, and functional logic necessary to perform the functions described herein. Implantation of the control unit 14' as shown in Figure 7 enables the catheter 12 to function as a permanent respiratory pacemaker. The programmer 98 allows the patient or healthcare professional to modify or program nerve stimulation or sensing parameters. The remote controller 16 can be used as described in relation to Figures 2 and 3. In other examples, the remote controller 16 may be in the form of a smartphone, tablet, wristwatch or other wearable device. The catheter 12 or multiple catheters can be inserted and positioned as described in relation to Figures 2, 3, 4A and 4B.

[0112] Once the catheter is fully inserted into the patient, various electrodes or combinations of electrodes are tested to locate the target nerve and determine which electrode most effectively stimulates it. For example, in one embodiment, testing is performed to locate the right phrenic nerve and determine which group of distal electrodes in the distal electrode assembly most effectively stimulates the right phrenic nerve. Similarly, testing is performed to locate the left phrenic nerve and determine which group of proximal electrodes in the proximal electrode assembly most effectively stimulates the left phrenic nerve. Likewise, testing is performed to locate the vagus nerve and determine which group of electrodes in the electrode assembly most effectively stimulates the vagus nerve.

[0113] This test and nerve position can be controlled and / or monitored via a control device 14 or 14', which may include test programming and / or applications. For example, the control device 14 or 14' may test electrodes and electrode combinations to determine which combination of electrodes (e.g., two-pole, three-pole, four-pole, multi-pole) most effectively stimulates a target nerve (e.g., right phrenic nerve, left phrenic nerve and / or vagus nerve).

[0114] As a non-limiting example, the test is performed using a signal generator that systematically delivers electrical impulses to selected electrodes. The desired stimulating electrodes can be identified by observing the patient's condition or by using sensors (in or separate from the catheter). The electrodes can function as both stimulating and sensing electrodes, and the medical system can be integrated within a ventilator, which can be used to detect the patient's condition. Furthermore, a control device, for example, can be programmed and / or activated to (a) select a first stimulating group of electrodes from the electrode assembly to stimulate the left phrenic nerve, (b) select a second stimulating group of electrodes from the electrode assembly to stimulate the right phrenic nerve, (c) select a third stimulating group of electrodes from the electrode assembly to stimulate the vagus nerve, (d) select a first stimulating current for the first stimulating group of electrodes to stimulate the left phrenic nerve, (e) select a second stimulating current for the second stimulating group of electrodes to stimulate the right phrenic nerve, and (f) select a third stimulating current for the third stimulating group of electrodes to stimulate the vagus nerve. The selection of electrodes and current levels can be pre-programmed or input based on patient characteristics, or the control device can test different electrode sets and current levels, monitor the patient's response, and determine the electrode pair and current level.

[0115] In some cases, the systems of this specification may include percutaneous non-invasive vagus nerve stimulators (nVNSs) and / or percutaneous respiratory muscle stimulators for stimulating the vagus nerve. For example, a device that uses current from a small portable or skin-attached device to stimulate a nerve in the neck or earlobe can be used to stimulate the vagus nerve or to stimulate nerves / muscles in the torso to move the respiratory muscles. Or, furthermore, various other methods can be used to stimulate nerves (e.g., subcutaneous electrodes or nerve cuffs connected to a control device).

[0116] When an electric charge is delivered to the phrenic nerve, the diaphragmatic muscle can contract, creating negative pressure in the pleural cavity. The lungs then expand to draw in air. This contraction of the diaphragmatic muscle can be detected manually by palpation or by placing a hand in the pleural cavity, as shown in Figure 2. Alternatively, respiratory activity can be detected by placing an airflow or airway pressure sensor in the breathing circuit, or by placing a sensor 16 (e.g., an accelerometer or gyroscope) on the surface of the skin in the chest region, as shown in Figure 2. Sensor 18 can be wired to a control device 18, or it can be connected using a wireless transmitter and receiver.

[0117] Figure 8, similar to Figure 1, shows the cervical and thoracic structures. Figure 8 further illustrates a typical medical system 200, including a transcutaneous electrode array 13. The array 13 includes a series of electrodes 44 placed on the patient's skin surface immediately proximal to the intercostal muscles. The electrodes 44 can have any preferred shape and size and can assist in various functions (e.g., detecting electrical activity through the skin and stimulating muscles or nerves). The electrodes 44 can include stainless steel, conductive carbon fiber reinforced ABS plastic, silver / silver chloride ion compounds, or any other preferred material, or any combination of materials. Each electrode 44 can be covered with a polymer film or elastomer film, which may include an adhesive for attaching the electrode 44 to the skin. Alternatively, the electrode film may contain an electrolyte gel for better signal conduction. In some embodiments, other forms of electrodes (e.g., subcutaneous or needle electrodes) can be used to stimulate the intercostal muscles, or the system can activate target nerves or muscles using other forms of stimulating energy (e.g., ultrasound).

[0118] Figure 8 further illustrates a transesophageal tube 46 comprising electrodes 48 on the tube (e.g., integrated with the tube) and / or on an inflatable balloon surrounding all or part of the tube 46. The electrodes 48 can be printed on the surface of the tube 46 (or balloon) using conductive ink (e.g., silver ink, gold ink, graphene ink, or carbon-based ink). Alternatively, the electrodes 48 can be formed by fixing electrode material (e.g., platinum iridium, stainless steel, titanium, or similar material) to the tube 46 using adhesive and connecting the electrodes 48 to the control device 18 with one or more wires. The electrodes 48 can be used to detect signals from the phrenic nerve or vagus nerve, or several other neurological elements. The electrodes 48 can also be used to stimulate nerves (e.g., at least one of the vagus nerve, phrenic nerve, or sympathetic ganglia) or the esophageal sphincter.

[0119] Alternatively, the system 200 in Figure 8 may include a catheter equipped with electrodes and / or sensors as described in Figure 2. To restore negative pressure ventilation, the system 200 can stimulate one or both phrenic nerves to stimulate the intercostal muscles and move the diaphragmatic muscle (as shown via electrode 44) to create negative pressure in the thoracic cavity or a compressive force into the thoracic cavity. The system may receive feedback by detecting the activity of the phrenic or vagus nerve from one of the electrodes on an intravascular catheter (if used) or a transesophageal tube 46. Feedback from nerve activity can be used to determine the stimulation parameters necessary to maintain proper ventilation and whether adjustment of the stimulation parameters is necessary. The system may also receive feedback from any other suitable sensors to determine the appropriate stimulation parameters. One or more of the following sensors may be included in either system 100 or system 200: airflow sensors, airway pressure sensors, accelerometers, gyroscopes, blood gas sensors, or sensors for detecting inflammatory substances. In some cases, System 100 or System 200 may include sensors for detecting inflammatory substances. Examples of such inflammatory substances include, but are not limited to, erythrocyte sedimentation rate (ESR), cytokines, C-reactive protein (CRP), plasma viscosity (PV), hemoglobin A1C, serum ferritin, red blood cell width, insulin, nitric oxide, or other biomarkers of inflammatory diseases (e.g., inflammatory bowel disease, Alzheimer's disease, Crohn's disease, arthritis, cancer, diabetes).

[0120] Figure 9 shows a block diagram of the various elements of the system. Electrodes, hubs, and lumens may be parts of the catheter described herein. A catheter may have any number of electrodes and any number of lumens. Five lumens are shown in Figure 9, but in different examples, a catheter may have one, two, three, four, or more than five lumens. In one example, a catheter may have three lumens (e.g., an expansion lumen and a corresponding internal lumen), each of which may hold one or more of a guidewire or fiber optic camera, or be used for fluid delivery or blood sample extraction. In another example, a catheter may have four lumens, one lumen holding or fluid-communicating with a pressure sensor, one lumen holding or fluid-communicating with a blood gas sensor, and the other two lumens holding or / or fluid-communicating with a guidewire or fiber optic camera, and / or being used for fluid delivery or blood sample extraction. It should be understood that any lumen of the system may contain, or be in fluid communication with, any of the devices described herein (e.g., sensors, guidewires, optical fiber cameras), and / or may be used for any of the functions described herein (e.g., fluid delivery, blood sample extraction).

[0121] The system may include a controller, which may be part of any of the control devices described herein. Each component of the system may be operably connected to the controller, which may manage the operation of electrodes during nerve stimulation, control the collection of information by various sensors and electrodes, and control fluid delivery or extraction. It should be understood that the various modules described herein may also be part of a computer system and are separated in Figure 9 for illustrative purposes only, and the modules do not need to be physically separated.

[0122] The electrodes can be electronically connected to a switching electronic device, which can then communicate with a controller. As shown in Figure 9, some of the electrodes may be distal electrodes and some may be proximal electrodes. Some electrodes can be placed in separate catheters. Hubs can also be connected to the switching electronic device and used as electrodes.

[0123] Electrodes can be used for both electrically stimulating nerves and collecting physiological information. When used for nerve stimulation, a first combination of electrodes (e.g., one, two, or more electrodes) can be electrically coupled to a first stimulation module channel for stimulating a first nerve (e.g., the right phrenic nerve), and a second combination of electrodes (e.g., one, two, or more electrodes) can be electrically coupled to a second stimulation module channel for stimulating a second nerve (e.g., the vagus nerve). A third or fourth channel may also be present to stimulate more nerves or muscles. Electrical signals can be sent from the first and second stimulation module channels to the electrode combinations to cause the electrodes to stimulate nerves. In other examples, combinations of more than two electrodes (e.g., three, four, or more) can be used to stimulate one or more target nerves, and the system may include more than two stimulation module channels.

[0124] The electrodes can be further configured to detect physiological information from the patient (e.g., neural activity, ECG, or electrical impedance), as will be described later. When used for detection, one or more electrodes can be electronically coupled to a signal acquisition module. The signal acquisition module can receive signals from the electrodes.

[0125] Switching electronic equipment can selectively connect electrodes to a first stimulation module channel, a second stimulation module channel, or a signal acquisition module. Switching electronic equipment can change which electrodes are used for stimulation and which are used for detection for any predetermined time. For example, any electrode can be used for nerve stimulation, and any electrode can be used for the detection function described herein. That is, each electrode can be configured to stimulate nerves, and each electrode can be configured to detect physiological information.

[0126] The signal acquisition module can be further connected to one or more sensors configured to collect physiological information from the patient. For example, the system may include one or more blood gas sensors or pressure sensors. These sensors can be placed in the lumen of the catheter, outside the patient with fluid communication to the lumen, on the outer surface of the catheter, or in any other preferred location. In one example, the blood gas sensor may be housed in or with fluid communication to the lumen, while the pressure sensor may be housed in or with fluid communication to another lumen. The blood gas sensor can measure the amount of O2 or CO2 in the patient's blood. The pressure sensor can measure the patient's central venous pressure (CVP).

[0127] The signal acquisition module can send signals received from one or more electrodes, blood gas sensors, and / or pressure sensors to the appropriate processing / filtering module of the system. For example, signals from a pressure sensor can be sent to a central venous pressure signal processing / filtering module, where the signals are processed and filtered to aid in the interpretation of CVP information. Similarly, signals from a blood gas sensor can be sent to a blood gas signal processing / filtering module for processing and filtering to determine blood gas levels. When used for detection, signals from electrodes can be sent to a nerve signal processing / filtering module, ECG signal processing / filtering module, or impedance signal processing / filtering module, as needed. Signals from electrodes or other sensors can be sent to an amplification module, where the signals can be amplified as needed before being sent to the appropriate processing / filtering module.

[0128] Typical methods for preventing or treating brain injury The systems and methods described herein can regulate the diaphragm and prevent, regulate, control, or treat brain injury, which may be caused by artificial respiration. The systems and methods can perform tests on brain function and / or vagus nerve stimulation status. Based on the test results, one or more phrenic nerves and / or vagus nerves can be stimulated. Nerve stimulation can reduce brain inflammation. Alternatively, one or more nerves (e.g., the vagus nerve) can be blocked using signals from electrodes to block abnormal signaling from the brain.

[0129] In a typical treatment session, the catheter 12 can be placed in a vascular structure adjacent to or extending over the left and right phrenic nerves 26, 28. Appropriate distal and proximal electrode pairs can be selected to produce contraction of the respiratory muscles (e.g., both left and right hemiphrenic muscles). The operator (e.g., physician or patient) can set the stimulation pulse train length to approximately 1.2 seconds, the pulse amplitude to approximately 100% of the threshold, and the initial pulse width to approximately 100% of the threshold. The pulse parameters can be adjusted with positive lung pressure from an external respiratory support device 88 to achieve the desired level of muscle contraction and reduction. The pulse width can be adjusted between stimulation pulses of the stimulation pulse train. In some cases, the pulse amplitude can be adjusted between stimulation pulses of the stimulation pulse train. Using a remote handheld controller 20, the operator can provide a treatment set of 10 stimulation pulse trains. In some examples, each stimulation pulse train can be timed to match the respiration delivered by a ventilator or the patient's spontaneous breathing.

[0130] In some embodiments, the system can communicate directly with a ventilator or other external respiratory support system (e.g., external respiratory support 88) to coordinate with assisted therapeutic delivery provided by the external device. As described above, activity detected by sensors from the diaphragmatic muscle, nerves (e.g., phrenic nerve, vagus nerve, etc.), other patient monitoring devices, or respiratory support devices can be used to induce stimulation and / or respiratory delivery from the ventilator. In a further non-limiting example, the system described herein can be operablely connected (e.g., wired, wireless, etc.) to receive signals from the ventilator indicating the initiation of breathing to the patient, and the system can synchronize the delivery of stimulation pulse trains to coordinate with the desired respiratory phase. In another example, the operator can set stimulation parameters to prompt the patient to move those respiratory muscles. The operator can then coordinate the triggering of electrical stimulation with the patient's effort to provide maximal muscle movement. In yet another example, the external respiratory support 88 can be reduced or even eliminated during part or all of the delivery of a stimulation set or stimulation session.

[0131] In some cases, a train of 10 stimulation pulses is provided. The pulse train can be timed to 10 consecutive breaths, or the operator may skip one or more breaths to allow the patient to rest periodically between stimulations. After the 10 stimulation pulse trains have been delivered, the patient is allowed to rest for a while (e.g., 30 seconds to 5 minutes). After adequate rest, the operator may initiate a second set (e.g., 10 breaths) followed by another rest period. The operator may deliver several sets (e.g., 4 sets), each containing 10 stimulations. Each stimulation can induce a total of 40 muscle contractions over a period of 1 to 15 minutes. The desired number of stimulations between sessions can be delivered in a single set as needed. The patient is then allowed to rest (e.g., for more than 1 hour) before starting another treatment session, and may be allowed to rest for a minimum of 3 hours, potentially 24 or 48 hours. In some cases, two or more treatment sessions are performed daily. Regardless, the number of stimuli delivered to the respiratory muscles may be only a small fraction of the breaths required by the patient each day. In the example of 40 stimuli / day mentioned above, the number of stimuli delivered is less than approximately 0.2% or about 0.2% of the breaths performed by the patient or the breaths delivered to the patient per day.

[0132] For example, the stimulation parameter may remain the same from one stimulus to the next, from one treatment set to the next, from one session to the next, or from one day to the next, to induce muscle contraction. In other examples, one of the parameters (e.g., stimulation amplitude, stimulation frequency, stimulation holding time, or respiratory circuit resistance) may be increased or decreased between two stimuli that induce muscle contraction, between two sets, between two sessions, or over two days. Factors to consider when changing the parameter may also be the patient's tolerance, unintended stimulation of other structures, fatigue, or a desire for increased intensity.

[0133] In another example of a treatment session, the stimulus signal may be delivered over an overall period of 2 hours or less during one or more treatment sessions, or over an overall period of approximately 2 hours or less within a 24-hour period. In yet another example, the stimulus signal may be delivered over an overall period of 5 hours or less within a 24-hour period.

[0134] In other examples of therapeutic sessions, stimulatory signals may be delivered to one or more respiratory muscles to produce contractions not exceeding 20% ​​of the respiration performed or delivered to the patient in a 24-hour period, not exceeding 10% of the respiration performed or delivered to the patient in a 24-hour period, not exceeding 2% of the respiration performed or delivered to the patient in a 24-hour period, or not exceeding 0.2% of the respiration performed or delivered to the patient in a 24-hour period.

[0135] In another example, short stimulation therapy sessions lasting approximately 3 to 10 minutes can be delivered 12 to 24 times over a 24-hour period, 8 to 12 times over a 24-hour period, or once every 24 hours.

[0136] In another example, treatment sessions can continue until the patient no longer requires external respiratory support, or up to 48 hours after the patient has not required or received external respiratory support.

[0137] Various examples of the present disclosure can be implemented shortly after a patient has begun using external respiratory support (e.g., mechanical ventilation) to help reduce the loss of strength and / or endurance of the respiratory muscles. Various examples of the present disclosure can be used to help reduce the level of damage to the patient's lungs, heart, brain, and / or other organs of the body. It is conceivable that stimulation coinciding with each breath, or with most breaths, can provide the desired level of protection.

[0138] The system described herein can be programmed to vary the profile of the stimulation pulse trains as needed. For example, each of the 10 stimulation pulse trains can be programmed to be longer than others in order to produce deeper or longer breaths (e.g., expiratory respiration). In this case, the duration of the stimulation pulse trains between two adjacent pulse trains will vary.

[0139] In some cases, treatment can be continued until the MIP reaches a predetermined value, and the steps related to activating and deactivating the stimulator can be repeated.

[0140] Furthermore, any treatment procedure described herein can be performed on one or more nerves and one or more respiratory muscles. The stimulation of multiple nerves (and one or more respiratory muscles) can be synchronized so that the patient's muscles(s) are stimulated simultaneously. To achieve this synchronization, two or more combinations of selected electrodes can be activated simultaneously during the treatment session. For example, if the first set of electrodes emits up to 100 electrical signals, the second set of electrodes can emit up to 100 electrical signals, with each emission of the second set corresponding to an emission of the first set of electrodes. In one example, the first and second sets of electrodes can be used to stimulate the left and right phrenic nerves to induce synchronized contraction of the left and right hemidiaphragms. In another example, the first set can be used to stimulate the diaphragm and the second set can be used to stimulate the intercostal muscles. The diaphragm and intercostal muscles can be stimulated simultaneously. Alternatively, the diaphragm and intercostal muscles can be stimulated in alternating phases. For example, when the external intercostal muscles are stimulated, the diaphragm can be stimulated simultaneously with them. When the internal intercostal muscles are stimulated, the diaphragm and internal intercostal muscles can be stimulated in opposite phases. Both stimulations can be performed simultaneously with the patient's respiratory cycle. In yet another example, the patient's nerves / muscles can be stimulated during the inspiratory phase of the patient's mechanical ventilation or other external respiratory support.

[0141] Most of the examples described herein involve treatment sessions performed by healthcare professionals, while other methods of therapeutic delivery may be available to build intensity by supplying irregular stimulation to the respiratory muscles. In a non-limiting example, a closed-loop automation of the systems of this disclosure may be designed to deliver stimulation to the respiratory muscles at a specific duty cycle (e.g., once per X breaths), where X can range from 10 to 1000. This method can provide periodic muscle stimulation, including a predetermined number of resting breaths in between. X can be as small as 1 and as large as 10,000 in various examples. When using the systems and methods described herein to prevent respiratory muscle atrophy and lung and brain injuries, stimulation can potentially be delivered as frequently as each breath.

[0142] Various electrodes can be used to stimulate nerves and / or muscles as described in this disclosure. For example, the stimulators described herein may include one or more of the following: nerve stimulating electrodes, endotracheal electrodes, endoesophageal electrodes, intravascular electrodes, transcutaneous electrodes, intradermal electrodes, electromagnetic beam electrodes, balloon electrodes, basket electrodes, umbrella electrodes, tape electrodes, suction electrodes, screw electrodes, spine electrodes, bipolar electrodes, monopolar electrodes, metallic electrodes, wire electrodes, patch electrodes, cuff electrodes, clip electrodes, needle electrodes, or probe electrodes. Furthermore, the stimulating energy may be delivered by an energy form including at least one of mechanical, electrical, ultrasonic, photon, or electromagnetic energy.

[0143] It should be understood that the intent of this disclosure is described herein in relation to exemplary embodiments of a particular application, and that such disclosure is not limited thereto. Anyone with access to the art well known and the teachings provided herein will understand that all additional modifications, uses, embodiments, and substitutions of equivalents fall within the scope of the embodiments described herein. Therefore, the present invention should not be considered limited by the foregoing description.

Claims

1. A stimulator configured to stimulate a first nerve and a second nerve, wherein the stimulation of the first nerve generates negative pressure in the target thoracic cavity, and the stimulation of the second nerve reduces inflammation, modulates vagus nerve signals, or reduces the level of factors contributing to brain damage. A processor configured to receive test results that reflect the state of the brain or vagal nerve activity of the subject, and to determine stimulation parameters based on the test results, A system in which the processor triggers the stimulator to stimulate the first nerve and the second nerve, and the first nerve is stimulated with a stimulation signal characterized by the stimulation parameters.

2. The system according to claim 1, wherein the processor is further configured to induce the stimulator to stimulate the second nerve with a stimulus signal characterized by the stimulus parameters.

3. The system according to claim 1, wherein the stimulation parameters include stimulation amount, number of pulses in the stimulation sequence, or respiratory rate.

4. The system according to claim 1, wherein determining the stimulus parameter based on the test results includes comparing the test results with a reference threshold or range.

5. The system according to claim 1, further configured to perform tests that generate the test results.

6. The system according to claim 5, wherein the test includes magnetic resonance imaging, computed tomography, magnetoencephalography, electroencephalography, blood flow measurement, blood pressure measurement, intracranial pressure measurement, cerebral oxygenation measurement, pupil diameter measurement, measurement of blood flow to the eye, measurement of the concentration of molecules in body fluids indicating brain damage or dysfunction, or a combination thereof.

7. The system according to claim 5, wherein the test includes measuring cerebral oxygenation by near-infrared spectroscopy of the fluid surrounding the brain of the subject.

8. The system according to any one of claims 1 to 5, wherein the stimulator is configured to receive signals from the vagus nerve, and the processor is configured to determine the test result from the signals.

9. The system according to any one of claims 1 to 5, further comprising a ventilator, wherein the test results include the effect of artificial respiration by the ventilator on the brain.

10. The system according to claim 9, wherein the ventilator is configured to provide respiratory assistance having volume and pressure, and the processor is configured to stimulate the stimulator to stimulate the second nerve during a portion of the inspiratory phase of respiration assisted by the ventilator.

11. The system according to claim 10, wherein the processor is further configured to adjust the volume or pressure of the respiratory support provided by the ventilator.

12. The system according to any one of claims 1 to 7, wherein the processor is further configured to determine the start of a respiratory event, the end of the respiratory event, or both, and to determine the timing of stimulating the first nerve, the timing of stimulating the second nerve, or both in relation to the respiratory event.

13. The system according to any one of claims 1 to 7, wherein stimulation of the second nerve modulates the vagus nerve signal, and the modification of the vagus nerve signal inhibits the transmission of abnormal signals by the vagus nerve.

14. The system according to any one of claims 1 to 7, wherein the first nerve is the phrenic nerve and the second nerve is the vagus nerve.

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