Methods and systems for respiratory stimulation

Abstract

Methods of stimulation may include measuring a cardiac event of a cardiac cycle and determining a first stimulation pattern based on the cardiac event. Methods of stimulation may also include delivering a stimulation signal to a nerve that innervates a respiratory muscle, where the stimulation signal is delivered according to the first stimulation pattern. The first stimulation pattern may include a primary stimulation signal and a secondary stimulation signal. Determining the first stimulation pattern may include includes determining a time when the secondary stimulation signal starts, relative to the measured cardiac event.

Description

Atorney Docket No. 00059-0022-00304METHODS AND SYSTEMS FOR RESPIRATORY STIMULATION CROSS-REFERENCE TO RELATED APPLICATONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 755,528, filed February 7, 2025, which is incorporated by reference in its entirety.

[0002] In general, all publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically indicated to be incorporated by reference. For example, embodiments of the present disclosure may be used in combination with one or more systems, catheters, stimulators, apparatuses, and electrodes described in U.S. Pat. No. 9,242,088; U.S. Pat. No. 9,333,363; U.S. Pat. No. 9,776,005; U.S. Pat. No. 10,039,920; U.S. Pat. No.10,293,164; U.S. Pat. No. 10,940,308; U.S. Pat. No. 10,987,511; U.S. Pat. No. 11,357,979; U.S. Pat. No. 11,771,900; U.S. Pat. No. 12,029,901; U.S. Pat. No. 12,029,903; U.S. Pat. Pub.2023 / 0023475; and / or WIPO Pub. No. 2024 / 100623; the disclosures of which are hereby incorporated by reference.INTRODUCTION

[0003] The embodiments of this disclosure generally relate to methods and devices (including systems) for the stimulation of nerves, muscles, and / or other tissue. More specifically, embodiments of the present disclosure include methods and sy stems for determining stimulation patterns and stimulating one or more respiratory nerves and / or muscles according to the deter ined stimulation patterns.SUMMARY

[0004] Embodiments of the present disclosure may be directed to a method for stimulating a respiratory' muscle. The method may comprise measuring a cardiac event of a cardiac cycle, determining a first stimulation pattern based on the cardiac event, and delivering a stimulation signal to a nerve that innervates a respiratory muscle. The stimulation signal may be delivered according to the first stimulation pattern.Atorney Docket No. 00059-0022-00304

[0005] In some embodiments of the present disclosure, the method for stimulation a respiratory muscle may further comprise measuring a respiratory event of a respiratory cycle.

[0006] The cardiac event may be a QRS electrocardiogram complex. The first stimulation patern may include a primary stimulation signal and a secondary stimulation signal.Determining the first stimulation patern may include determining a time when the secondary stimulation signal starts, relative to the measured cardiac event. Determining the first stimulation patern may include determining a time when the primary stimulation signal ends, relative to a measured respiratory event. The secondary stimulation signal may start after an end of the primary stimulation signal. The primary stimulation signal may include a plurality of stimulation pulses. The secondary stimulation signal may include a plurality of secondary stimulation pulses. The number of primary stimulation pulses may be greater than the number of secondary stimulation pulses.

[0007] Embodiments of the present disclosure may be directed to a method for stimulating a respiratory muscle. The method may include placing a stimulation lead in a subject. The stimulation lead may include at least one electrode and / or at least one sensor. The method for stimulating a respiratory muscle may include detecting, via the at least one sensor, a respiratory event. In some embodiments, the method for stimulating a respiratory muscle may include detecting, via the at least one sensor, a cardiac event. The method may further include determining a first stimulation patern based on the respiratory event and the cardiac event. The first stimulation patern may include a primary stimulation signal and a secondary stimulation signal. The method may further include applying, via the at least one electrode, the primary stimulation signal to a nerve that innervates a respiratory muscle and / or applying, via the at least one electrode, the secondary stimulation signal to the nerve. Applying the primary stimulation signal to the nerve may generate negative pressure in a thoracic cavity of a subject.

[0008] In some embodiments of the present disclosure a method for stimulation a respiratory muscle may further include detecting a second respiratory event, detecting a second cardiacAtorney Docket No. 00059-0022-00304event, determining a second stimulation patern based on the second respiratory event, the second cardiac event, and the first respiratory event. The second respiratory event and / or the second cardiac event may be detected via the at least one electrode and / or at least one sensor. The second stimulation patern may include a third stimulation signal and a fourth stimulation signal. A method for stimulation of a respiratory muscle may further include providing respiratory support to the subject via an external respiratory device. A method for stimulation of a respiratory muscle may include applying the third stimulation signal to the nerve and / or applying the fourth stimulation signal to the nerve. The third stimulation signal and / or the fourth stimulation signal may be applied via the at least one electrode. Applying the third stimulation signal to the nerve may generate negative pressure in the thoracic cavity of the subject. Ceasing stimulation of the third stimulation signal to the nerve may increase the pressure in the thoracic cavity. A duration of the third stimulation signal may be shorter than a duration of the fourth stimulation signal. The first stimulation patern may be determined based on one or more of the respiratory event, the cardiac event, historical respiratory cycle data, and historical cardiac cycle data. The stimulation patern may include a duration between the primary stimulation signal and the secondary stimulation signal. The stimulation patern may further include a number of pulses in the primary stimulation signal, a duration of the primary stimulation signal, an amplitude of at least one pulse in the primary stimulation signal, a frequency of the primary stimulation signal, a pulse width of the primary stimulation signal, or a combination thereof. A duration of the primary stimulation signal may be shorter than a duration of the secondary stimulation signal. The cardiac sound may be a QRS electrocardiogram complex.

[0009] Embodiments of the present disclosure may be directed to a stimulation system. The system may include a stimulation lead configured for intravascular, subcutaneous, and / or topical placement. The stimulation lead may include at least one electrode and / or at least one sensor. The at least one sensor may be configured to measure respiratory data and cardiac data. The system may further include a controller in communication with the at least one sensor and / or aAtorney Docket No. 00059-0022-00304signal generator electrically connected to the controller and the at least one electrode. The controller may be configured to determine a stimulation patern based on respiratory data and cardiac data received from the at least one sensor and / or cause the signal generator to deliver an electrical signal to the at least one electrode. The stimulation patern may include a primary stimulation signal, a secondary stimulation signal, and a duration between the primary stimulation signal and the secondary stimulation signal. The electrical signal may be delivered according to the stimulation patern.

[0010] In some embodiments of the present disclosure the at least one sensor is at least one of a, airway flow / pressure sensor, a motion sensor, an electrogram sensor, an impedance sensor, an electromyography sensor, a camera or visual -based sensor, a sound based sensor, a temperature sensor, a pressure sensor, a blood flow sensor, a blood volume sensor, a blood gas sensor, or an electromagnetic sensor. The controller may be further configured to cause the signal generator to deliver the electrical signal in a timed relationship with the cardiac data and / or cause the signal generator to deliver the electrical signal in a timed relationship with the respiratory data.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The accompanying drawings, which are incorporated in and constitute part of this specification, illustrate non-limiting embodiments of the present disclosure and together with the description, serve to explain the principles of the disclosure.

[0012] FIGs. 1A-1C illustrate flowcharts of exemplary stimulation methods, according to one or more embodiments;

[0013] FIG. 2 illustrates characteristics of an exemplary stimulation patern and associated physiological responses, according to one or more embodiments;

[0014] FIG. 3 illustrates an exemplary stimulation lead, according to one or more embodiments;

[0015] FIG. 4 illustrates exemplary components of a stimulation system including a transvascular stimulation lead, according to one or more embodiments;Atorney Docket No. 00059-0022-00304

[0016] FIG. 5 illustrates exemplary components of a stimulation system including a transcutaneous stimulation lead, according to one or more embodiments;

[0017] FIG. 6 illustrates exemplary components of a stimulation system including an endotracheal stimulation lead, according to one or more embodiments; and

[0018] FIG. 7 illustrates an exemplary architecture of a stimulation system, according to one or more embodiments.DETAILED DESCRIPTION

[0019] Embodiments of the present disclosure include methods and respiratory stimulation systems. Methods and systems of the present disclosure may be configured to stimulate one or more anatomical targets, such as for example, one or more nerves that innervate a respiratory muscle. The stimulation of one or more nerves that innervate a respiratory muscle may cause movement of one or more respiratory muscles. Stimulation of anatomical targets may be configured to assist or cause contraction of one or more respiratory muscles. Stimulation that assists or causes contraction of one or more respiratory muscles may provide ventilatory assistance to a subject. Respiratory muscles may include a diaphragm, intercostal muscles (e.g., internal intercostal muscles and external intercostal muscles, inspiratory accessory muscles (e.g., sternocleidomastoid muscle, scalene muscles, pectoralis muscles, serratus anterior, tassiumus dorsi, serratus posterior superior, ilicostalis cervicis); expiratory accessory muscles (e.g., rectus abdominis, external oblique, internal oblique, transversus abdominis, iliocostalis, longissiumus, serratus posterior inferior, quadratus lumborum), and / or one or more other muscles connected to a thoracic cage.

[0020] Stimulation methods and systems described herein may modulate hemodynamic performance of a heart. As used herein, modulating hemodynamic performance of a heart may refer to changing, adjusting, altering, increasing, or decreasing, a chemical activity of a heart, a heart muscle contraction amplitude, a cardiac load (e.g., a preload and / or a post load), and / or anAtorney Docket No. 00059-0022-00304electrical activity of a heart. The modulation of hemodynamic performance of a heart may result in beter outcomes in critical and non-critical patients.

[0021] The respiratory system of a subject is responsible for the exchange of carbon dioxide and oxygen between the subject and the atmosphere. This exchange may be referred to as the respiratory cycle. Characteristics of the respiratory cycle (e.g., rate, inspiration time, expiration time, pressure, volume, and / or quality of breaths taken by the subject) affect the relative levels of carbon dioxide and oxygen within the subject. The respiratory cycle affects the respiratory system, the cardiovascular system, other tissues, and can affect physiological, behavioral, and cognitive processes.

[0022] The respiratory cycle includes an inspiration phase and an expiration phase. The respiratory cycle may include a pause between an inspiration phase and a subsequent expiration phase. This pause may be referred to as an inspiration pause. In addition or alternatively, the respiratory cycle may include a pause between an expiration phase and a subsequent inspiration phase. This pause may be referred to as an expiration pause. During the inspiration phase, the diaphragm may move from a medial position to a caudal position, thereby increasing a volume of the thoracic cavity, and / or decreasing the thoracic pressure, causing lungs to expand and fdl with gas. During the expiration phase, the diaphragm may move from a medial position to a cranial position, thereby decreasing a volume of, and or increasing the pressure within the thoracic cavity, causing gas to exit the lungs. During the inspiration phase, the intercostal muscles (e.g., the external intercostal muscles), may contract to lift the rib cage upwards and outwards, expanding the thoracic cavity and facilitating inhalation. Also during the inspiration phase, the accessory muscles (e.g., the sternocleidomastoid muscles and the scalene muscles) may provide additional inhalatory force by further elevating the ribs. During the expiration phase, the intercostal muscles may relax, allowing the rib cage to descend, thereby pushing air out of the lungs. Also during the expiration phase, accessory muscles (e.g., the abdominal muscles) may contract to forcefully expel air (e.g., during heavy breathing).Atorney Docket No. 00059-0022-00304

[0023] A respiratory cycle may be measured, tracked, recorded, monitored, and / or characterized by one or more measurements that track the flow of gas during the respiratory cycle. For example, aspects of a subject’s respiratory cycle may be measured by an airflow sensor, an airway pressure sensor, a motion sensor, an impedance sensor, a camera or visual-based detection, and / or sound based detection.

[0024] As described herein, a stimulation patern may be determined that includes stimulation during one or more positions within a respiratory cycle. Positions in a respiratory cycle may be defined based on their proximity to one or more events of a respiratory cycle. Events of the respiratory cycle may include a beginning of an inspiration phase, an end of an inspiration phase, a beginning of an inspiration pause, an end of an inspiration pause, a beginning of an expiration phase, an end of an expiration phase, a beginning of an expiration pause, and / or an end of an expiration pause. Exemplary positions include times before, after, and during respiratory events. For example, a position in a respiratory cycle may be defined based on a respiratory event that occurs at the position, an amount of time between a prior respiratory event and the position, or an amount of time between the position and a subsequent respiratory event.

[0025] A cardiac cycle describes the function of a heart from the initiation of one heartbeat to the initiation of a subsequent heartbeat. The cardiac cycle may include an atrial systole phase and an atrial diastole phase. The cardiac cycle may further include a ventricular diastole phase that overlaps with at least a portion of the atrial systole phase and / or at least a portion of the atrial diastole phase. The cardiac cycle may also include a ventricular systole phase that overlaps with at least a portion of the atrial systole phase and / or at least a portion of the atrial diastole phase. The ventricular diastole phase may refer to a portion of the cardiac cycle where a ventricle relaxes and fills with blood. The ventricular systole phase may refer to a portion of the cardiac cycle where a ventricle contracts and pumps blood out of the heart.

[0026] The cardiac cycle may include an isovolumetric relaxation (part of the ventricular diastole phase and the atrial diastole phase), a ventricular filling (part of the ventricular diastoleAtorney Docket No. 00059-0022-00304phase and the atrial diastole phase) after the isovolumetric relaxation, an atrial contraction (part of the ventricular diastole phase and the atrial systole phase) after the ventricular filling, an isovolumetric contraction (part of the ventricular diastole phase and the atrial diastole phase) after the atrial contraction, and / or a ventricular ejection (part of the ventricular diastole phase and the atrial diastole phase) after the isovolumetric contraction.

[0027] During the isovolumetric relaxation, ventricles and atriums of the heart relax, the atrioventricular valves are closed, and the semilunar valves are closed, allowing blood to enter the heart. During the ventricular filling, the atrioventricular valves are open, and the semilunar valves are closed, allowing blood to enter the ventricles. During atrial contraction, the atriums of the heart contract, the atrioventricular valves are open, and the semilunar valves closed, allowing blood to flow from the atriums to the ventricles. During isovolumetric contraction, the ventricles contract, the atrioventricular valves are closed, and the semilunar valves are closed. During ventricular ejection, the ventricles are contracted, the atrioventricular valves are closed, and the semilunar valves are open, allowing blood to exit the heart.

[0028] Under typical resting conditions, the cardiac cycle has a duration of approximately 0.7 seconds to approximately 1.0 second. A cardiac cycle may be measured, tracked, recorded, monitored, and / or characterized by one or more measurements. For example, a cardiac cycle may be characterized via an electrocardiogram. The electrocardiogram (ECG) may include a three lead ECG, a twelve lead ECG, an internal vascular ECG, a subcutaneous ECG, an external ECG, or other suitable arrangements of ECG leads. In addition or alternatively, the cardiac cycle may be characterized by measuring a central venous pressure, measuring blood oxygenation, measuring blood pressure, measuring blood flow, measuring arterial pressure, and / or measuring venous pressure. In some embodiments, optical sensors, a camera and visual -based algorithms, and / or sound based algorithms may be utilized in characterizing the cardiac cycle.

[0029] As described herein, a stimulation patern may be determined that includes stimulation during one or more positions within a cardiac cycle. Positions in a cardiac cycle may be definedAtorney Docket No. 00059-0022-00304based on their proximity to one or more events of a cardiac cycle. Events of the cardiac cycle may include a beginning of an atrial systole phase, an end of an atrial systole phase, a beginning of an atrial diastole phase, an end of an atrial diastole phase, a beginning of a ventricular diastole phase, an end of a ventricular diastole phase, a beginning of an ventricular systole phase, an end of a ventricular systole phase, an isovolumetric relaxation, a ventricular filling, an atrial contraction, an isovolumetric contraction, a ventricular ejection, a contraction of a ventricle, a contraction of an atrium, a relaxation of a ventricle, a relaxation of an atrium, a cardiac valve (e.g., an atrioventricular valve, a semilunar valve) opening, a cardiac valve closing, a p-wave of an ECG, a Q-wave of an ECG, an R-wave of an ECG, an S-wave of an ECG, a QRS spike of an ECG, a t-wave of an ECG, an SI heart sound, and / or an S2 heart sound. Exemplary positions include times before, after, and during cardiac events. For example, a position in a cardiac cycle may be defined based on a cardiac event that occurs at the position, an amount of time between a prior cardiac event and the position, or an amount of time between the position and a subsequent cardiac event. In some embodiments, cardiac events determined from an ECG may be the preferred reference for determining position in the cardiac cycle, as the ECG may provide a more accurate signal with reduced delay between the event and detection of the event. In addition or alternatively, an intravascular electrocardiogram may be readily available from electrodes configured for stimulation, allowing for detection of ECG signals with a lower number of structures and / or components.

[0030] In some embodiments, a cardiac activity may be measured and a determination may be made that cardiac assistance (e.g., increased cardiac assistance) is indicated. A cardiac activity may be quantified by Doppler ultrasound, echocardiogram, the Fick Principle, athermal dilution, an arterial blood pressure analysis, a blood oxygenation analysis, a blood flow rate, a cardiac stroke volume, an impedance, an internal ECG, or an external ECG.

[0031] A Doppler ultrasound cardiac activity assessment may refer to a medical procedure that uses ultrasound technology to evaluate the function and structure of the heart. For example, aAtorney Docket No. 00059-0022-00304healthcare professional or other user may be able to visualize movement of one or more portions of a heart and / or blood flow within the heart chambers and valves using sounds waves. An echocardiogram may be generated from the Doppler ultrasound cardiac activity assessment. Doppler ultrasound cardiac activity assessment (e.g., an echocardiogram generated from Doppler ultrasound cardiac activity assessment) may be used to measure a heart chamber size, measure an activity of a heart valve, measure motion of one or more heart chamber walls, and / or measure a velocity of a blood flow through the heart. Measurements made during an Doppler ultrasound cardiac activity assessment may diagnose and / or characterize potential heart problems, sources of chest pain, sources of abnormal heart sounds. In addition or alternatively, measurements made during an Doppler ultrasound cardiac activity assessment may be used to evaluate cardiac function after a heart attack and / or monitor progression of heart disease.

[0032] The Fick principle may refer to a method used to assess cardiac activity by calculating cardiac output based on an amount of oxygen consumed by the subject (e.g., VO2) and / or a difference in oxygen content between arterial and venous blood. Assessing cardiac activity using the Fick principle may generate a cardiac output value which is representative of the volume of blood pumped by the heart per minute and / or an amount of oxygen being delivered to tissue per minute. Relatively higher cardiac output values correspond to a relatively greater amount of oxygen being delivered to tissue. The Fick principle may be applied in various conditions of the subject including heart failure, exercise testing, prior to a treatment being applied, after a treatment is applied and / or during surgery. For example, a cardiac output measured via the Fick principle during one patient condition (e.g., after a treatment is applied) may be compared to a cardiac output measured during another patient condition (e.g., before treatment is applied) to determine how the varying conditions affect cardiac output.

[0033] Cardiac activity assessment by thermal dilution may refer to a method that measures cardiac output (e.g., a volume of blood pumped by the heart per minute) by injecting a known volume of a cold fluid (e.g., saline) into a first position (e.g., the right atrium) within or near theAtorney Docket No. 00059-0022-00304heart. After the known volume of cold fluid is injected, the temperature change in blood at a second position (e.g., within the pulmonary artery) within or near the heart may be measured. The degree of temperature change measured may be inversely proportional to the cardiac output. For example, a portion of a catheter may include a temperature sensor (e.g., a thermistor) placed in a pulmonary artery. The temperature change detected by the temperature sensor, after a cold fluid is delivered via the catheter, may be used to calculate a cardiac output based on the Stewart-Hamilton equation. The cardiac output determined by thermal dilution may be used to assess cardiac function in critical condition subjects (e.g., subjects experiencing shock, heart failure, and / or undergoing surgery, such as a cardiac catheterization procedure). In addition or alternatively, the cardiac output determined by thermal dilution may be used to assess the impact of a valve dysfunction on cardiac output.

[0034] A cardiac activity assessment of cardiac stroke volume may refer to an evaluation of an amount (e.g., mass or volume) of blood a heart pumps with each beat. For example, a stroke volume may refer to a volume of blood ejected during a cardiac cycle. Stroke volume may be representative of an amount of blood pumped out of a heart ventricle with each contraction. In some embodiments, a stroke volume may be calculated by subtracting an end-systolic volume from an end-diastolic volume. Stroke volume may be determined from an echocardiogram or a cardiac catheterization. The cardiac catheterization may include directly measuring blood pressure and flow within heart chambers. Directly measuring blood pressure and flow within heart chambers may provide more detailed information about stroke volume, compared to other methods. Stroke volume may be an important indicator of a heart’s pumping efficiency and / or overall cardiac function of a subject. For example, a decreased stroke volume can indicate cardiac dysfunction, such as heart failure or another cause of the heart not effectively pumping blood. An increased stroke volume may be representative of a subject’s increased oxygen demand.Atorney Docket No. 00059-0022-00304

[0035] External respiratory support may be indicated for critically ill subjects. Examples of external respiratory support include mechanical ventilation, high flow oxygen, continuous positive airway pressure (CPAP), bilevel positive airway pressure (Bi-PAP), and / or extracorporeal membrane oxygenation (ECMO). External respiratory support may include pushing air in lungs under positive pressure. The associated positive pressure may cause unintended damage to the respiratory and / or cardiac systems. For example, due to the use of positive pressure during inhalation, mechanical ventilation may be associated with damage to structures within the lungs. Positive pressure mechanical ventilation may negatively impact the heart by decreasing cardiac output due to reduced venous return caused by increased intrathoracic pressure, essentially hindering the right ventricle's ability to fdl properly, which can lead to hypotension and decreased tissue perfusion. The negative effects of positive pressure mechanical ventilation can be more pronounced in subjects with pre-existing cardiac issues. In addition or alternatively, the positive pressure may result in an increased load on the heart due to a decreased preload, an increased afterload, a reduced cardiac output, and / or ventricular dysfunction. The increased intrathoracic pressure during positive pressure ventilation may compress the vena cava, reducing the amount of blood returning to the right atrium, thereby decreasing the preload. In certain situations, positive pressure ventilation may increase pulmonary vascular resistance, which acts as an increased afterload for the right ventricle. The combined effects of decreased preload and potentially increased afterload may lead to a significant reduction in cardiac output. In critically ill subjects with compromised cardiac function, positive pressure ventilation may increase ventricular dysfunction.

[0036] Embodiments of the present disclosure include methods and systems for modulating hemodynamic performance of a heart. For example, methods of the present disclosure may include providing stimulation to one or more anatomical targets, thereby generating negative pressure in a thoracic cavity of the subject and reducing the load on the heart. In some embodiments of the present disclosure, the methods and / or systems described herein may beAtorney Docket No. 00059-0022-00304provided with or without external respiratory support. In subjects without external respiratory support, stimulations in sync with cardiac cycle may be applied.

[0037] In further examples, providing stimulation to one or more anatomical targets using the methods and / or systems described herein may result in improved venous return, lowered blood pressure, decreased heart rate, enhanced heart rate variability (HRV), stress reduction, etc. Applications of the methods described herein (e.g., stimulation of the diaphragm) may create negative pressure in the chest cavity, which draws blood back to the heart, increasing stroke volume. Diaphragmatic breathing may help regulate blood pressure by promoting relaxation and reducing sympathetic nervous system activity, and may decrease stress hormones like cortisol, leading to a calmer state. By stimulating the parasympathetic nervous system through deep breathing, the diaphragm may contribute to a slower heart rate and enhanced HRV. An enhanced HRV may indicate a good balance between the sympathetic and parasympathetic nervous systems. As described herein, one or more stimulation signals may be delivered to one or more anatomical targets according to a stimulation patern. The stimulation patern may include stimulation parameters of one or more stimulation signals. For example, a stimulation patern may include a primary stimulation signal delivered to a first target, a secondary stimulation signal delivered to the first target, a primary stimulation signal delivered to a second target, and / or a secondary stimulation signal delivered to the second target. Each stimulation signal may include one or more stimulation pulses. Parameters of each stimulation signal may include: a start time of the stimulation signal, relative to one or more respiratory events; a start time of the stimulation signal, relative to one or more cardiac events; an end time of the stimulation signal, relative to one or more respiratory events; an end time of the stimulation signal, relative to one or more cardiac events; a duration of the stimulation signal; a frequency of the stimulation signal; a number of pulses in the stimulation signal; an amplitude of one or more pulses of the stimulation signal; and / or a pulse width of the stimulation signal.Atorney Docket No. 00059-0022-00304

[0038] Values for parameters of each stimulation signal may be generated or determined based on data received from one or more sensors regarding aspects of a respiratory cycle, data received from one or more sensors regarding aspects of a cardiac cycle, historical respiratory data, and / or historical cardiac data. For example, methods of stimulation described herein may include measuring a cardiac event (e.g., an SI heart sound), and determining a timing of a stimulation signal (e.g., a secondary stimulation signal) relative to the cardiac event.

[0039] Referring to FIG. 1A, an exemplary stimulation method 400 may include measuring a respiratory event of a respiratory cycle (step 402), measuring a cardiac event of a cardiac cycle (step 404), and generating a stimulation patern (step 406). As described herein, one or more sensors of a stimulation system may be configured to measure a respiratory event of a respiratory cycle and / or measuring a cardiac event of a cardiac cycle. Method 400 may include generating a stimulation patern based on the measured respiratory event, the measured cardiac event, or both. Generating a stimulation patern may include determining values of one or more stimulation parameters of a stimulation signal. For example, a start time of the stimulation signal, relative to one or more cardiac or respiratory events and / or an end time of the stimulation signal, relative to one or more cardiac or respiratory events may be determined based on the measured respiratory event, the measured cardiac event, historical respiratory data, historical cardiac data, or a combination thereof.

[0040] Referring to FIG. IB, an exemplary stimulation method 420 may include stimulating an anatomical target according to a first stimulation patern (step 422), assessing cardiac function (step 424), and generating a second stimulation patern (step 426). For example, the second stimulation patern may be generated based on the assessed cardiac function. In one or more embodiments, the first stimulation patern may include only primary stimulation pulses. Based on an assessment that cardiac function is not at optimal levels, a second stimulation patern may be generated that includes primary stimulation pulses and secondary stimulation pulses.Atorney Docket No. 00059-0022-00304

[0041] Referring to FIG. 1C, an exemplary stimulation method 440 may include stimulating a respiratory nerve according to a first stimulation patern (step 442), measuring a respiratory event of a respiratory cycle (step 444), measuring a cardiac event of a cardiac cycle (step 446), generating a second stimulation patern (step 448), and stimulating a respiratory nerve according to the second stimulation patern (step 450). In one or more embodiments, the first stimulation patern may include a primary stimulation signal, a secondary stimulation signal, and a time between the primary stimulation signal and a secondary stimulation signal. Based on the measured respiratory event, the measured cardiac event, historical respiratory data, historical cardiac data, or a combination thereof, a second stimulation patern may be generated that includes a shorter or longer time between the primary stimulation signal and the secondary stimulation signal, compared to the first stimulation patern.

[0042] Referring to FIG. 2, an exemplary stimulation patern may be applied during one or more respiratory cycles. The stimulation patern shown in FIG. 2 includes a stimulation signal (e.g., a primary stimulation signal) delivered to a first anatomical target every respiratory cycle, shown in the first electrical stimulation level row. The stimulation patern shown in FIG. 2 also includes a primary stimulation signal (e.g., between time To and time T2) and a secondary stimulation signal (e.g., between time T2 and time T4) delivered to a second anatomical target. The first charge Ci, and second charge C2, may correspond to an amount of charge within the stimulation signal. First charge Ci may be equivalent to a current of about 27 milliamps, a pulse width of about 300 microseconds, and / or a frequency of about 40 Hertz. Second charge C2 may be equivalent to a current of about 1 milliamp, a pulse width of about 20 microseconds, and / or a frequency of about 4 Hertz. In the example shown in FIG. 2, the first anatomical target is a right phrenic nerve of a subject and the second anatomical target is a left phrenic nerve of the subject.

[0043] In some embodiments, the timing of the stimulation patern shown in FIG. 2 may be relative to the inspiratory phase with a stimulation duration that matches or is less than the inspiration time, and / or relative to the cardiac cycle during the P-wave or start of QRS complexAtorney Docket No. 00059-0022-00304with a relatively short stimulation duration (e.g., milliseconds). Cardiac cycle stimulation may reduce thoracic cavity pressure to assist the preload phase of the cardiac cycle.

[0044] In some embodiments where a subject is receiving positive pressure respiratory assistance, stimulation may be provided in one of two ways. In a first way, negative pressure may be reduced by stimulating the left and / or right hemidiaphragm during the inspiratory cycle of the positive pressure respiratory assistance. The diaphragm contractions may be in the physiological range that can generate occlusion pressure of 5 to 10 cm of water. A second way may apply the stimulation manner of the first with the added stimulation of the left and / or right hemidiaphragm for short duration aligned with the cardiac cycle. For example, stimulation may be applied during ventricular relaxation to provide some negative pressure of 1 to 2 cm of water, and may provide extra room for ventricles to expand and may relax the diaphragm during the ventricular contraction. For subjects on positive pressure respiratory assistance, the stimulation synchronized with cardiac cycle may be enough to generate negative pressure of 1 to 2 cm of water so that a breath is not triggered during the expiration phase of positive pressure device.

[0045] In some embodiments, for subjects not on positive pressure respiratory assistance, stimulation may be provided by stimulating the left and / or right hemidiaphragm for short duration aligned with the cardiac cycle. For example, stimulation may be applied during ventricular relaxation to provide some negative pressure of 1 to 5 cm of water, and may provide extra room for ventricles to expand and may relax the diaphragm during the ventricular contraction.

[0046] In some embodiments, there may be a ratio of amplitudes, durations, pulse widths, number of pulses, etc. between the different types of stimulation. The range of amplitude for both type of stimulations can be 0.1 mA to 30 mA, 0.1 mA to 50 mA, or any other suitable range. The pulse width range for respiratory stimulation, for example, may be between 50 microseconds to 400 microseconds. The pulse width range for stimulation synchronized with cardiac cycle may be between 10 microseconds to 600 microseconds. The frequency range forAtorney Docket No. 00059-0022-00304respiratory stimulation may be between 15 Hz and 40 Hz. The frequency range for stimulation synchronized with cardiac cycle may be between 1 Hz to 40 Hz. The stimulation duration range for respiratory stimulation may be between 0.1 second to 5 seconds. The stimulation duration range for stimulation synchronized with cardiac cycle may be between 100 microseconds to 0.2 seconds.

[0047] The physiological responses to the stimulations are also shown in FIG. 2. For example, FIG. 2 shows the induced movement of the right hemidiaphragm and the left hemidiaphragm of the subject, as a result of the stimulation signals. As shown in FIG. 2, the primary stimulation signals cause a deep caudal movement of the diaphragm, thereby generating negative pressure in the thoracic cavity of the subject, and allowing gas to flow into the lungs of the subject. Further, the secondary stimulation signals cause twitch movements of the left hemidiaphragm. While these twitch movements may not result in the subject’s lungs filling with gas, the twitch movements may modulate hemodynamic performance of a heart and / or decrease a load of the heart. The flow, pressure, and lung volume shown in FIG. 2 indicate that inspiration occurs as a result of the primary stimulation signals, but does not occur as a result of the secondary stimulation signals. Additionally, FIG. 2 indicates that cardiac cycle of the subject (measured by ECG) does not align with the respiratory cycle of the subject (measured by flow, pressure, and volume) for a first breath between time To and time T4, or for a second breath between time T4 and Te. After secondary stimulation signals were delivered during the first and second breaths, the cardiac cycle of the subject aligns with the respiratory cycle of the subject. For example, during a third breath between time Te and time T7, and during a fourth breath between time T7 and time Ts, a p-wave of the ECG aligns with the beginning of inspiration. Accordingly, the delivery of primary and secondary stimulation signals may synchronize the cardiac cycle and the respiratory cycle of the subject.

[0048] As indicated in FIG. 2, the stimulation patern may be repeated for multiple respiratory cycles (e.g., a first cycle from time To to time T4 and a second respiratory cycle from time T4 toAtorney Docket No. 00059-0022-00304time Te). The stimulation patern shown in FIG. 2 is merely one example. Those of ordinary skill in the art will understand that other stimulation paterns including stimulation parameters having different values than those shown in FIG. 2 are within the scope of the disclosure.

[0049] Methods described herein may be performed with a stimulation system. The stimulation system may include a stimulation lead, a controller, and / or a signal generator. In some embodiments, the stimulation system may include an external respiration device (e.g., a mechanical ventilator). The stimulation system may be configured to determine stimulation paterns (e.g., based on a measured respiratory event and / or a measured cardiac event) and deliver stimulation signals according to the determined stimulation paterns. For example, the controller of stimulation system may be configured to execute one or more steps of the methods described herein.

[0050] The stimulation lead may be in communication (e.g., wired or wireless) with the controller of the stimulation system. The stimulation lead may transmit data received from the one or more sensors to the controller. The controller may determine a stimulation patern. For example, the controller may determine a stimulation patern based on data received from the one or more sensors, from historical data stored on a memory accessible to the controller, and / or from one or more user inputs. The controller may induce the signal generator to deliver a stimulation signal through the stimulation lead (e.g., via the one or more electrodes of the stimulation lead) to an anatomical target (e.g., one or more nerves innervating a respiratory muscle). The controller may induce the signal generator to deliver the stimulation signal according to a determined stimulation patern.

[0051] The stimulation lead may be configured for intravascular placement, endotracheal placement, and / or transcutaneous placement. The stimulation lead may include at least one electrode and at least one sensor. In some embodiments, the stimulation lead may further include one or more lumens, one or more electrical connectors, one or more ports, one or more heatingAtorney Docket No. 00059-0022-00304elements, one or more thermistors, and / or one or more placement structures (e.g., an inflatable member).

[0052] Referring to FIG. 3, an exemplary stimulation lead 200 may include a proximal portion 250, a distal portion 270, and a medial portion 260 between the proximal portion 250 and the distal portion 270. Stimulation lead 200 (e.g., a proximal portion 250 of stimulation lead 200) may include one or more inlets 222. One or more inlets 222 may be connected to a lumen defined within a body 226 of stimulation lead 200. For example, one or more inlets may be connected to a proximal end of a lumen defined within body 226 of stimulation lead 200. One or more inlets 222 may comprise a luer or other type of connection that allows for a seal between an external device or component and inlet 222. Stimulation lead 200 (e.g., proximal portion 250 of stimulation lead 200) may include an electrical connector 224. Electrical connector 224 may be configured to connect at least one other device, system, or component to stimulation lead 200. Signals received by stimulation lead 200 (e.g., signals received by one or more electrodes or sensors within stimulation lead 200) may be transmited to a controller via electrical connector 224. In addition or alternatively, signals (e.g., stimulation signals) from a controller or signal generator may be transmited to stimulation lead 200 (e.g., one or more electrodes of stimulation lead 200) via electrical connector 224. The one or more inlets 222 and / or electrical connector 224 may be coupled to the rest of stimulation lead 200 via a junction box 228 disposed within a proximal portion 250 of stimulation lead 200.

[0053] Stimulation lead may include one or more ports, such as, for example, a tip port 202, a distal port 204, a medial port 206, and / or a proximal port 208. A lumen defined within body 226 of stimulation lead 200 may extend from an inlet 222 to a port (e.g., tip port 202, distal port 204, medial port 206, and / or proximal port 208).

[0054] As described herein one or more ports (e.g., tip port 202, distal port 204, medial port 206, and / or proximal port 208) may be in fluid communication with one or more lumens defined within body 226. One or more sensors, such as, for example, a pressure sensor and / or a bloodAtorney Docket No. 00059-0022-00304oxygen sensor may be disposed within one or more of the lumens. The pressure sensor and / or blood oxygen sensor may record pressure and / or blood oxygen data and transmit the pressure and / or blood oxygen data to another device, system, and / or component (e.g., a controller). A fluid delivery device may interface with one or more inlets 222 such that the fluid delivery device can deliver fluid to tip port 202, distal port 204, medial port 206, and / or proximal port 208.

[0055] Stimulation lead 200 may include a temperature sensor 214 and / or a heating element 216. For example, a distal portion 270 of stimulation lead 200 may include temperature sensor 214 and / or heating element 216. Temperature sensor 214 may be positioned between a distal end (e.g., tip port 202) of stimulation lead 200 and heating element 216. Temperature sensor 214 may be configured to measure temperature data and / or transmit temperature data to other devices, systems, or components (e.g., a controller). In some embodiments, temperature sensor 214 may be a thermistor. In some embodiments, heating element 216 may be used for thermodilution. For example, where a catheter may be injecting cold fluid into the bloodstream (e.g., as part of a system to measure cardiac output), heating element 216 may provide a consistent baseline temperature for comparison against the injected cold fluid. The downstream temperature change due to the injected cold fluid may be detected, and heating element 216 may precisely warm the blood to facilitate accurate temperature measurements. In some embodiments, upstream electrodes may be used as resistive elements to heat the blood for some period of time (e.g., timed with the cardiac cycle), and a downstream thermal sensor(s) may be used to measure the temperature fluctuation.

[0056] Stimulation lead 200 may include one or more proximal electrodes 220. For example, proximal electrodes 220 may be positioned at different longitudinal and / or radial positions along proximal portion of 250. Stimulation lead 200 may include one or more distal electrodes 218. Distal electrodes 218 may be positioned between a distal end (e.g., tip port 202) of stimulationAtorney Docket No. 00059-0022-00304lead 200 and proximal electrodes 220. For example, distal electrodes may be positioned at different longitudinal and / or radial positions along medial portion 260 of stimulation lead 200.

[0057] One or more proximal electrodes 220 may be configured to deliver a stimulation signal received from a signal generator to an anatomical target. For example, a stimulation signal may be delivered from a multipolar combination of proximal electrodes 220. In some embodiments, one or more proximal electrodes 220 may be configured to receive a signal from tissue, such as, for example, an impedance and / or an ECG signal. One or more distal electrodes 218 may be configured to deliver a stimulation signal received from a signal generator to an anatomical target. For example, a stimulation signal may be delivered from a multipolar combination of distal electrodes 218. In some embodiments, one or more distal electrodes 218 may be configured to receive a signal from tissue, such as, for example, an impedance and / or an ECG signal.

[0058] Still referring to FIG. 3, stimulation lead 200 may include an inflatable member 210. Inflatable member 210 may be positioned within a distal portion 270 of stimulation lead 200. Inflatable member 210 may be positioned between a distal end (e.g., tip port 202) of stimulation lead 200 and temperature sensor 214. Inflatable member 210 may be configured to assist with placement / anchoring of stimulation lead 200 in a blood vessel. In some embodiments, inflatable member 210 may be configured to control blood flow. For example, inflatable member 210 may be expanded or contracted to adjust a blood flow when stimulation lead 200 is positioned within the vasculature of a subject.

[0059] Stimulation lead may include a pressure sensor 212. Pressure sensor 212 may be positioned on a distal portion 270 of stimulation lead 200. For example, pressure sensor 212 may be supported on inflatable member 210. Pressure sensor 212 may be configured to measure pressure data and / or transmit the pressure data to other devices, systems, and / or components (e.g., a controller).Atorney Docket No. 00059-0022-00304

[0060] Referring to FIG. 4, a stimulation system may include a stimulation lead 200, an external respiratory device 104, a controller 108, and a signal generator (not pictured). The signal generator may be included within stimulation lead 200 or may be within a housing that includes controller 108. As shown in FIG. 4, stimulation lead 200 may be placed within a vasculature of a subject such that one or more proximal electrodes 220 are proximate a left phrenic nerve 116 and one or more distal electrodes 218 are proximate a right phrenic nerve 110. For example, stimulation lead 200 may be positioned such that at least a portion of stimulation lead 200 is in a jugular vein, at least a portion of stimulation lead 200 is within a superior vena cava, at least a portion of stimulation lead 200 is within a heart, and / or at least a portion of stimulation lead 200 is within a pulmonary artery. Stimulation lead 200 may be inserted into vasculature through an incision in a subject’s neck orthorax. In one or more embodiments, stimulation lead 200 is positioned such that inflatable member 210, distal port 202, and temperature sensor 214 are within a pulmonary artery, distal port 204 and at least a portion of heating element 216 are within a heart, one or more distal electrodes 218 are within a superior vena cava, and one or more proximal electrodes 220 are within a jugular vein.

[0061] Referring to FIG. 5, a stimulation system may include a first transcutaneous stimulation lead 132a, a second transcutaneous stimulation lead 132b, a controller 108, a first abdominal sensor 134a, and / or a second abdominal sensor 134b. The first transcutaneous stimulation lead 132a and / or the second transcutaneous stimulation lead 132b may include one or more electrodes 219. The first transcutaneous stimulation lead 132a, the second transcutaneous stimulation lead 132b, or both, may be positioned below or within skin of a subject such that one or more electrodes 219 are proximate a left phrenic nerve 114, a right phrenic nerve 110, or both. One or more abdominal sensors 134a, 134b may be placed on or below the skin of a subject, such as, for example, proximate a diaphragm. First abdominal sensor 134a, second abdominal sensor 134b, or both may be configured to determine if an anatomical target is being stimulated. For example, if an anatomical target includes a right phrenic nerve 110, firstAtorney Docket No. 00059-0022-00304abdominal sensor 134a may determine if a stimulation signal delivered via an electrode 219 of the first transcutaneous stimulation lead 132a induced movement of a right hemi-diaphragm. In addition or alternatively, if an anatomical target includes a left phrenic nerve 114, second abdominal sensor 134b may determine if a stimulation signal delivered via an electrode 219 of the second transcutaneous stimulation lead 132b induced movement of a left hemi-diaphragm. In some embodiments, first abdominal sensor 134a, second abdominal sensor 134b, or both, comprises an accelerometer configured to detect movement of a diaphragm (e.g., of a portion of a diaphragm). Each transcutaneous stimulation lead 132a, 132b may be in wireless communication with controller 108, and / or one or more abdominal sensors 134a, 134b. Each abdominal sensor 134a, 134b may be in wireless communication with controller 108.

[0062] Referring to FIG. 6, a stimulation system may include an endotracheal stimulation lead 138 comprising one or more electrodes 219, an external respiratory support device 104, a controller 108, and / or one or more thoracic sensors 136. The endotracheal stimulation lead 138 may be positioned within a trachea of a subject such that one or more electrodes 219 are proximate a left phrenic nerve 116, a right phrenic nerve 110, or both. The thoracic sensors 136 may be placed on or under skin of a subject. For example, thoracic sensors 136 may be placed proximate one or more respiratory structures (e.g., one or more respiratory muscles and / or one or more lungs). Thoracic sensors 136 may measure an impedance and may transmit impedance data to endotracheal stimulation lead 138 and / or controller 108. In some embodiments, multiple thoracic sensors 136 may be placed at different positions along one or more lungs. Based on impedance measurements received from the one or more thoracic sensors 136, controller 108 may determine one or more characteristics of a respiratory cycle.

[0063] Referring to FIG. 7, an exemplary architecture of a stimulation system may include an internal communication bus 508 and / or switching electronics 340 that direct the flow of electrical energy and / or data within the stimulation system. In some embodiments, the at least one sensor may include a pressure sensor 326a, a blood gas sensor 326b, a thermal sensor 326c,Attorney Docket No. 00059-0022-00304an oxygen sensor 326d, at least one motion sensor 326e, 326f, and / or an arterial pressure sensor 326g.

[0064] The at least one sensor may transmit data to at least one module. In some embodiments, the at least one module may include a signal acquisition module 332a, at least one stimulation module 332b, 332c, an impedance module 332d, an oxygen sensor module 332e, a temperature sensing module 332f, a heating module 332g, an amplification module 332h, an electrocardiogram (EKG) module 332i, a central venous pressure module 332j , a video processing module 332k, an audio processing module 3321, an arterial pressure module 332m, and / or a motion sensor module 332n. The data transmitted and / or received may be stored via data storage 316.

[0065] Signal acquisition module 332a, at least one stimulation module 332b, 332c, and / or impedance module 332d may be configured to transmit and / or receive data from pressure sensor 326a, blood gas sensor 326b, and / or at least one electrode 328a, 328b, 328c, 328d, 328e, 328f, 328g, 328h, 328i, 328j, etc. At least one stimulation module 332b, 332c may be a signal generator configured to determine at least one stimulation pattern. For example, at least one stimulation module 332b, 332c may be configured to determine at least one simulation pattern based on respiratory data and cardiac data received from the at least one sensor. The stimulation pattern may include a first stimulation, a second stimulation, and / or a duration between the first stimulation and the second stimulation.

[0066] Oxygen sensor module 332e may be configured to transmit and / or receive data from at least oxygen sensor 326d. Temperature sensing module 332f may be configured to transmit and / or receive data from at least thermal sensor 326c. Heating module 332g may be configured to transmit and / or receive data from at least one electrode, e.g., a heating electrode 328k or heating element 216. Arterial pressure module 332m may be configured to transmit and / or receive data from at least arterial pressure sensor 326g. Motion sensor module 332n may be configured to transmit and / or receive data from at least at least one motion sensor 326e, 326f.Atorney Docket No. 00059-0022-00304

[0067] In some embodiments, at least one supplemental device 322 may interact with stimulation lead 200, one or more transcutaneous stimulation leads 132a, 132b, and / or an endotracheal stimulation lead 138. The at least one supplemental device 322 may connect to stimulation lead 200 via at least one lumen / port 324a, 324b, 324c, 324d, 324e, 324f. For example, where at least one supplemental device 322 is an optical fiber camera, the optical fiber camera may be connected to stimulation lead 200 via at least one lumen / port 324a, 324b, 324c, 324d, 324e, 324f. Data from the optical fiber camera may be transmited to video processing module 332k, a display 314, etc. via an electrical connection with at least one lumen / port 324a, 324b, 324c, 324d, 324e, 324f.

[0068] As described herein, a stimulation system may include a controller 108. Controller 108 may comprise a computer including, for example, a data communication interface for packet data communication. The controller 108 may also include a central processing unit (CPU), in the form of one or more processors, for executing program instructions. The controller 108 may be in communication with internal communication bus 508 and / or data storage 316 (e.g., ROM, HDD, SDD, or other structure that stores data on a computer readable medium). The data storage 316 may store instructions for executing techniques presented herein, although the instructions may be stored temporarily or permanently within other modules of the stimulation system.

[0069] Controller 108 may receive programming and data via network communications. The controller 108 also may include input and output ports and / or a display to connect with input and output devices such as keyboards, mice, remote controls, touchscreens, monitors, displays, or similar input and output devices. The various system functions may be implemented in a distributed fashion on a number of similar platforms, to distribute the processing load.Alternatively, the systems may be implemented by appropriate programming of one computer hardware platform.Atorney Docket No. 00059-0022-00304

[0070] The different embodiments of the stimulation system may be used for temporary or short term therapy, e.g., the stimulation electrodes are readable removable after a period of time. As such, rather than permanent therapies where the systems require invasive surgery to place and / or remove the device, the different embodiments of the stimulation system may be easily removed without the necessity of invasive and / or potentially dangerous surgery.

[0071] The different embodiments of the various stimulation system components may be combined and used together in any logical arrangement. Furthermore, individual features or elements of any described embodiment may be combined with or used in connect with the individual features or elements of other embodiments. It will be apparent to those skilled in the art that various modifications and variations may be made in the disclosed devices and methods without departing from the scope of the disclose. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the features disclosed herein. It is intended that the specification be considered as exemplary only.

Claims

Attorney Docket No. 00059-0022-00304CLAIMSWhat is claimed is:

1. A method for stimulating a respiratory muscle, comprising:measuring a cardiac event of a cardiac cycle;determining a first stimulation pattern based on the cardiac event; anddelivering a stimulation signal to a nerve that innervates a respiratory muscle, where the stimulation signal is delivered according to the first stimulation pattern.

2. The method of claim 1, wherein the cardiac event is a QRS electrocardiogram complex.

3. The method of claim 1, wherein the first stimulation pattern includes a primary stimulation signal and a secondary stimulation signal.

4. The method of claim 3, wherein determining the first stimulation pattern includes determining a time when the secondary stimulation signal starts, relative to the measured cardiac event.

5. The method of claim 3, further comprising measuring a respiratory event of a respiratory cycle, wherein determining the first stimulation pattern includes determining a time when the primary stimulation signal ends, relative to the measured respiratory event.

6. The method of claim 3, wherein the secondary stimulation signal starts after an end of the primary stimulation signal.

7. The method of claim 3, wherein the primary stimulation signal includes a plurality of primary stimulation pulses, the secondary stimulation signal includes a plurality of secondaryAtorney Docket No. 00059-0022-00304stimulation pulses, and the number of primary stimulation pulses is greater than the number of secondary stimulation pulses.

8. A method for stimulating a respiratory muscle, comprising:placing a stimulation lead in a subject, the stimulation lead including:at least one electrode; andat least one sensor;detecting, via the at least one sensor, a respiratory event;detecting, via the at least one sensor, a cardiac event;determining a first stimulation patern based on the respiratory event and the cardiac event, wherein the first stimulation patern includes a primary stimulation signal and a secondary stimulation signal;applying, via the at least one electrode, the primary stimulation signal to a nerve that innervates a respiratory muscle, wherein applying the primary stimulation signal to the nerve generates negative pressure in a thoracic cavity of the subject; andapplying, via the at least one electrode, the secondary stimulation signal to the nerve.

9. The method of claim 8, wherein the stimulation patern is determined based on one or more of the respiratory event, the cardiac event, historical respiratory cycle data, and historical cardiac cycle data.

10. The method of claim 8, wherein the stimulation patern includes a duration between the primary stimulation signal and the secondary stimulation signal.

11. The method of claim 10, wherein the stimulation patern further includes a number of pulses in the primary stimulation signal, a duration of the primary stimulation signal, anAtorney Docket No. 00059-0022-00304amplitude of at least one pulse in the primary stimulation signal, a frequency of the primary stimulation signal, a pulse width of the primary stimulation signal, or a combination thereof.

12. The method of claim 8, wherein a duration of the primary stimulation signal is shorter than a duration of the secondary stimulation signal.

13. The method of claim 8, wherein the respiratory event is a first respiratory event, the cardiac event is a first cardiac event, and the method further comprises:detecting, via the at least one sensor, a second respiratory event;detecting, via the at least one sensor, a second cardiac event;determining a second stimulation patern based on the second respiratory event, the second cardiac event, and the first respiratory event, wherein the second stimulation patern includes a third stimulation signal and a fourth stimulation signal;applying, via the at least one electrode, the third stimulation signal to the nerve, wherein applying the third stimulation signal to the nerve generates negative pressure in the thoracic cavity of the subject; andapplying, via the at least one electrode, the fourth stimulation signal to the nerve.

14. The method of claim 13, wherein a duration of the third stimulation signal is shorter than a duration of the fourth stimulation signal.

15. The method of claim 8, wherein the cardiac event is a QRS electrocardiogram complex.

16. The method of claim 8, further comprising providing respiratory support to the subject via an external respiratory device.Atorney Docket No. 00059-0022-0030417. A stimulation system comprising:a stimulation lead configured for intravascular placement, wherein the stimulation lead comprises:at least one electrode; andat least one sensor, wherein the at least one sensor is configured to measure respiratory data and cardiac data;a controller in communication with the at least one sensor; anda signal generator electrically connected to the controller and the at least one electrode; wherein the controller is configured to:determine a stimulation patern based on respiratory data and cardiac data received from the at least one sensor, wherein the stimulation patern includes a primary stimulation signal, a secondary stimulation signal, and a duration between the primary stimulation signal and the secondary stimulation signal; andcause the signal generator to deliver an electrical signal to the at least one electrode, wherein the electrical signal is delivered according to the stimulation patern.

18. The stimulation system of claim 17, wherein the at least one sensor is at least one of a temperature sensor, a pressure sensor, a blood gas sensor, or an electromagnetic sensor.

19. The stimulation system of claim 17, wherein the controller is further configured to cause the signal generator to deliver the electrical signal in a timed relationship with the cardiac data.

20. The stimulation system of claim 17, wherein the controller is further configured to cause the signal generator to deliver the electrical signal in a timed relationship with the respiratory data.

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