Transvascular diaphragm pacing systems and methods of use

Abstract

To provide transvascular diaphragm pacing systems (TDPS) and methods for providing respiratory therapy to a patient.SOLUTION: The TDPS can provide rapid insertion and deployment of endovascular pacing electrodes in critically ill patients who require intubation and invasive PPMV in order to support the physiological requirements of the human ventilatory system. The systems and methods make best use of the contractile properties of the diaphragm muscle and prevent muscle disuse atrophy and muscle atrophy. This can be carried out by engaging the phrenic nerves using patterned functional electrical stimulation applied to endovascular electrodes that are temporarily and reversibly inserted in central veins of the patient, such as the left subclavian vein and the superior vena cava. The TDPS can be designed to seamlessly interface with any commercially available positive-pressure ventilatory assistance / support devices such as those commonly in use in hospital intensive care units (ICU) for treating critically ill patients with breathing insufficiency, pain, trauma, sepsis, neurological diseases or deficits, or the like.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a transvascular diaphragm pacing system and a method of using the same.

Background Art

[0002] Patients in the intensive care unit (ICU) of a hospital may have a reduced ability to breathe voluntarily due to their underlying medical conditions and may require positive pressure mechanical ventilation (PPMV) for ventilation assistance. PPMV is commonly used daily in the ICU in combination with the administration of sedatives to provide ventilation for these critically ill individuals. In addition, many patients who undergo surgery under general anesthesia in, for example, the operating room (OR) of a hospital, or who receive treatment under anesthesia or in a sedated state in, for example, the emergency room (ER) of a hospital, typically require PPMV for ventilation assistance while they are anesthetized or receiving sedatives.

[0003] Mechanical ventilation is a life support method, but when combined with the administration of sedatives or anesthesia, it interferes with the active contraction of the diaphragm. Prolonged, fully controlled mechanical ventilation can completely eliminate the neural activation and mechanical activity of the diaphragm, and can also induce muscle atrophy, proteolysis, and the release of reactive oxygen species, leading to a rapid loss of diaphragm function, a syndrome known as ventilator-induced diaphragmatic dysfunction (VIDD).

[0004] The onset of diaphragmatic disuse atrophy is rapid, delaying the patient's recovery, resulting in increased dependence on the ventilator, higher incidence of ventilator-associated pneumonia and nosocomial infections, longer stays in the ICU, and increased hospitalization costs.

[0005] In addition to ICU patients, mechanical ventilation is a major method of ventilation assistance for individuals with medical conditions such as spinal cord injury (SCI) that have an adverse effect on neurological function. These patients may have a reduced ability to breathe voluntarily due to partial or complete loss of control of the diaphragm and are often likely to be dependent on a mechanical ventilator for life.

[0006] Several viable alternatives to PPMV for assisting breathing are currently available and have been presented for use in patients who require long-term ventilation assistance, such as patients with spinal cord injury (SCI) or congenital central hypoventilation syndrome (CCHS). These include phrenic nerve stimulation and diaphragm pacing. In these methods, electrical stimulation is used, which employs electrodes and an external pacing control box or an implanted pacemaker device to induce contraction of the diaphragm.

[0007] The two phrenic nerves that control the activation of the diaphragm pass through the chest along the left and right sides of the heart and reach the diaphragm. Phrenic nerve stimulation is performed by electrically stimulating the phrenic nerve that controls the patient's diaphragm, whereby the breathing cycle can be induced. Conventional techniques include implanting a nerve cuff around the phrenic nerve (at the level of the neck or chest) and then delivering electrical stimulation from an externally placed controller through the cuff to the phrenic nerve. This procedure is very invasive, requires an incision when placing the nerve cuff, and is very costly, so it is selectively used only in patients who require lifelong assisted breathing. In addition, directly placing a nerve cuff around the phrenic nerve can damage the phrenic nerve. These phrenic nerve stimulation systems have not been previously prescribed for temporary use in critically ill ICU patients.

[0008] Other phrenic nerve stimulation techniques are also known (such as those described in Patent Document 1). However, the system disclosed in Patent Document 1 is not suitable for short-term, acute use, especially in the first few days after the initiation of PPMV, in the ICU environment for the management of ICU patients.

[0009] Another way to electrically stimulate the diaphragm is known as diaphragm pacing. Conventionally, diaphragm pacing has been performed by laparoscopically implanting four electrodes directly into the diaphragm (two on each side), with electrical leads connected to a controller located outside the body. Conventional diaphragm pacing procedures are also very time-consuming and quite invasive, requiring an incision during implantation, and carry the risks of the implantation procedure and chronic infection at the site where the leads enter the body. Therefore, these diaphragm pacing systems have not heretofore been prescribed for temporary use in critically ill ICU patients.

[0010] One such diaphragm pacing system is described in Patent Document 2. In addition to being surgically overly laborious, the diaphragm pacing system of Patent Document 2 is used to perform a treatment that converts type IIa (fast-twitch) muscle fibers to type I (slow-twitch) muscle fibers in patients who have been on long-term mechanical ventilation and whose muscle fibers have all atrophied and converted to fast-twitch (VIDD). However, the treatment described in Patent Document 2 is not desirable for the treatment of critically ill patients who still have both type IIa (fast-twitch) muscle fibers and type I (slow-twitch) muscle fibers, and it is necessary to successfully wean both types from PPMV.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0012] Therefore, there is a need for a minimally invasive diaphragm pacing system and method for acute short-term use, as appropriate in the ICU environment, particularly for the management of ICU patients in the days or weeks following the initiation of PPMV.

Means for Solving the Problem

[0013] In various examples of the systems and methods disclosed herein, among other things, to address this need, a minimally invasive nerve stimulation system is provided that transvascularly paces the phrenic nerve via a disposable intravascular electrode that can be placed percutaneously under local anesthesia. As will be described in "Best Mode for Carrying Out the Invention", short-term electrical stimulation can be applied using such pacing systems and methods to prevent diaphragmatic disuse atrophy in patients at risk of becoming ventilator-dependent and / or to reverse diaphragmatic disuse atrophy in ventilator-dependent patients.

[0014] This system is designed to operate with a mechanical ventilator to produce diaphragmatic contractions that are synchronized with each breath provided by the ventilator and intermittently synchronized with some ventilator breaths, or to operate as a stand-alone system. In some embodiments, this system and method can be used for just a few minutes or hours after the patient's initial intubation. Such diaphragmatic pacing therapy is expected to prevent, reduce or reverse diaphragmatic disuse atrophy typically occurring in patients on PPMV or patients expected to require long-term PPMV and sedation, and furthermore, the adverse effects associated with PPMV are avoided or reduced. As a result, the patient can successfully wean from PPMV earlier than with currently known methods, which brings significant health benefits to the patient and, needless to say, a substantial reduction in the total inpatient cost.

[0015] According to one aspect of the present disclosure, there is provided a method for implementing a treatment plan designed to prevent or reverse diaphragmatic disuse atrophy in a patient receiving respiratory assistance from a ventilator. The ventilator is used to provide a respiratory cycle to a patient having a prescribed level of assistance. The method includes monitoring the respiratory cycle of the ventilator, applying a pre-programmed stimulation signal to the patient to assist the patient's phrenic nerve, and adjusting the patient's diaphragmatic output for each respiratory cycle. In some embodiments, the stimulation signal is applied via one or more intravascular electrodes.

[0016] According to a first embodiment, the administration of the stimulation signal can be performed within a period such as 1 hour, 3 hours, 6 hours, 12 hours, 1 day, 3 days, and 1 week after the patient first receives respiratory assistance from the ventilator.

[0017] According to a second embodiment, the method further includes obtaining data representing at least one of one or more ventilator respiratory parameters, one or more pacing parameters, and the level of assistance prescribed for the patient.

[0018] According to a third embodiment, the one or more ventilator respiratory parameters include timing data representing the duration of the breaths being ventilated. According to a fourth embodiment, the method further includes maintaining synchronization between the delivery of the stimulation signal and the ventilator respiratory cycle.

[0019] According to a fifth embodiment, the step of maintaining synchronization includes determining the current respiratory cycle based on data from one or more sensors and comparing the current respiratory cycle with the timing data of at least one previous respiratory cycle.

[0020] According to a sixth embodiment, the diaphragmatic assistance provides at least a portion of the prescribed level of assistance. According to the seventh embodiment, the method further includes a step of determining the diaphragm contribution level by administering a stimulation signal, and the prescribed assist level is the sum of the diaphragm contribution level and the ventilator contribution level.

[0021] According to the eighth embodiment, the stimulation signal includes stimulation signal characteristics that will satisfy the diaphragm contribution level when the stimulation signal is sent to the patient. According to the ninth embodiment, the diaphragm contribution level is measured separately, together, and including these components for tidal volume or pressure.

[0022] According to the tenth embodiment, the prescribed diaphragm contribution level depends on the patient's medical condition, and contractile ability, and / or the functional state of the diaphragm. According to the eleventh embodiment, the step of determining the contractile ability includes the step of measuring strength and durability from the response of the diaphragm and examining the stimulation pattern.

[0023] According to the twelfth embodiment, the patient's medical condition, and the contractile ability of the diaphragm, and / or the functional state of the phrenic nerve are evaluated before and / or during the administration of the treatment plan. According to the thirteenth embodiment, the step of determining the strength and durability of the patient's diaphragm includes the step of measuring the maximum diaphragm output and fatigue characteristics of the diaphragm.

[0024] According to the fourteenth embodiment, the step of monitoring the respiratory cycle includes the step of detecting respiratory cycle data by a respiratory sensor that is separate from but connected to the respiratory circuit of the ventilator and the patient airway, and the step of determining the inhalation phase and exhalation phase of the respiratory cycle, and the duration of each phase from the detected respiratory cycle data.

[0025] According to the fifteenth embodiment, the step of monitoring the respiratory cycle further includes the step of determining at least one of the amplitude and change rate of the ventilator output signal for each breath. According to the 16th embodiment, the step of administering a stimulation signal includes the step of generating a stimulation signal according to one or more pacing parameters and the step of delivering the stimulation signal in relation to the ventilator breathing cycle.

[0026] According to the 17th embodiment, the step of adjusting the patient's diaphragm output for each breathing cycle such as a paced breathing cycle includes the step of monitoring the diaphragm output according to the last administered stimulation signal and the step of comparing the diaphragm output of the last administered stimulation signal with a preset target range. As an alternative, this method can skip the pacing of one breathing cycle (only MV), but can stimulate in the next breathing cycle (i.e., mechanical ventilation and diaphragm pacing). In this method, next, both of these values can be compared, and then the breathing to be paced can be adjusted.

[0027] According to the 18th embodiment, the step of monitoring the diaphragm output according to the last administered stimulation signal includes the step of detecting, by one or more sensors, one or more of the diaphragm output data representing one or more of the parameters derived from the air flow rate, tidal volume, pressure, and / or a combination of flow rate, tidal volume and / or pressure, and the step of processing the detected diaphragm data to determine the diaphragm output.

[0028] According to the 19th embodiment, the step of adjusting the patient's diaphragm output for each breathing cycle further includes the step of modifying the stimulation signal to be administered with the next ventilator breath when the diaphragm output of the last administered stimulation signal is outside the preselected target range.

[0029] According to the 20th embodiment, the preselected target range includes a diaphragm contribution level. According to the 21st embodiment, this method further includes the step of clarifying the cause when the diaphragm output of the last administered stimulation signal is outside the preselected target range.

[0030] According to the 22nd embodiment, when the cause is a change in the patient's respiratory mechanism, the state of the patient's diaphragm and respiratory system is evaluated during the administration of the treatment plan. According to the 23rd embodiment, this method further includes the step of reprogramming the stimulation signal based on the evaluated state of the diaphragm.

[0031] According to the 24th embodiment, the step of evaluating the diaphragm includes monitoring data representing the flow rate and pressure of the ventilator breathing cycle to determine the timing of end-expiratory delay, gradually stimulating the diaphragm using a stimulation signal based on the monitored data of the ventilator breathing cycle, and determining one or more functional characteristics of the diaphragm and respiratory system, where the one or more functional characteristics include one or more of maximum static inspiratory pressure, inspiratory volume, work of breathing, pressure-time integral, pressure-time index, electromyogram (EMG), maximum relaxation rate, and expiratory time constant.

[0032] According to the 25th embodiment, diaphragm stimulation is targeted to be performed during each ventilator breath to reduce positive pressure and the risk of ventilator-induced lung injury (VILI). According to the 26th embodiment, the step of monitoring the ventilator breathing cycle includes detecting signals representing the inspiration and expiration of the ventilator and calculating one or more of the inspiratory phase, expiratory phase, inspiratory pause, and expiratory pause.

[0033] According to the 27th embodiment, the step of administering the stimulation signal includes sending the stimulation signal simultaneously with the inspiratory phase. According to another aspect of the present disclosure, a transvascular diaphragmatic pacing system is provided that prevents or reverses diaphragmatic disuse atrophy in patients receiving respiratory assistance from a ventilator. The system includes at least one intravascular electrode configured to deliver a supplied stimulation signal. The stimulation signal is configured to assist the patient's phrenic nerve in some embodiments, and the stimulation signal has one or more stimulation parameters in some embodiments. The system also includes one or more sensors configured to detect a respiratory cycle signal from an attendant ventilator and a diaphragmatic response with phrenic nerve assistance, a pulse generator coupled to be electrically connected to the at least one intravascular electrode, and at least one input device configured to input data representing one or more aspects of a treatment plan. The system further includes a controller coupled to be electrically connected to the one or more sensors, the at least one input device, and the pulse generator. The controller receives input data representing one or more aspects of a treatment plan, including sensed signals representing ventilator operation parameters and one or more pacing parameters in some embodiments, monitors the respiratory cycle signal, determines an inspiration phase and an expiration phase of the respiratory cycle, generates a stimulation signal in response to the one or more pacing parameters, and sends the generated stimulation signal to the at least one transvascular electrode at a preselected time of the mechanical ventilation cycle, and is programmed to adjust the patient's diaphragmatic output for each respiratory cycle.

[0034] According to the 28th embodiment, the controller is further programmed to adjust the patient's diaphragmatic output to meet the patient's prescribed level of assistance. According to the 29th embodiment, the controller is further programmed to maintain synchronization between the delivery of the stimulation signal and the ventilator respiratory cycle.

[0035] According to the 30th embodiment, the controller is further programmed to monitor the diaphragmatic output in response to the last administered stimulation signal and compare the diaphragmatic output of the last administered stimulation signal to a preselected target range.

[0036] According to the 31st embodiment, the controller is programmed to monitor the diaphragm output by detecting the diaphragm output data by one of one or more sensors, processing the detected diaphragm data, and determining the diaphragm output, which includes parameters derived from flow rate, tidal volume, and / or pressure, and / or a combination of flow rate, tidal volume, and / or pressure.

[0037] According to the 32nd embodiment, the controller is further programmed to modify the stimulation signal to be administered with the next ventilator breath if the diaphragm output of the last administered stimulation signal is outside the preselected range. Alternatively, since some ventilator breaths may be skipped between stimulations, the signal can be modified and administered during the next breath with the programmed pacing (i.e., combined breathing).

[0038] According to the 33rd embodiment, the controller is further programmed to identify the cause if the diaphragm output of the last administered stimulation signal is outside the preselected target range.

[0039] According to the 34th embodiment, if the controller determines that the cause is due to a change in the patient's respiratory mechanism, the controller is further programmed to evaluate the state of the patient's diaphragm and respiratory system during the administration of the treatment plan.

[0040] According to the 35th embodiment, the controller is further programmed to reprogram the stimulation signal based on the evaluated state of the diaphragm. According to the 36th embodiment, the controller is further programmed to monitor data representing the flow rate and pressure of the ventilator breathing cycle to determine the timing of end-expiratory delay, gradually stimulate the diaphragm using a stimulation signal based on the monitored data of the ventilator breathing cycle, and evaluate the diaphragm by determining one or more functional characteristics of the diaphragm and the respiratory system. In some embodiments, the one or more functional characteristics include one or more of maximum inspiratory static pressure, inspiratory capacity, work of breathing, pressure-time product, pressure-time index, EMG, maximum relaxation rate, and expiratory time constant.

[0041] According to the 37th embodiment, the controller is further programmed to determine the ease of weaning from the ventilator based on the evaluation of the diaphragm. According to the 38th embodiment, the stimulation signal includes a pair of pulses or a triplet of pulses at the beginning of the stimulation train or in the middle of the stimulation train.

[0042] According to another aspect of the present disclosure, a method for preventing respiratory disuse atrophy in a patient wearing a ventilator and receiving ventilator breathing cycle respiratory assistance and sedation is provided. The method includes placing a first electrode within a vascular structure near the patient's left phrenic nerve, placing a second electrode within a vascular structure near the patient's right phrenic nerve, and transmitting a pre-programmed stimulation signal to the first and second electrodes to stimulate the diaphragm in synchronization with the ventilator breathing cycle within a few hours after the patient is wearing the ventilator.

[0043] According to the 39th embodiment, within a few hours includes one of within 12 hours, within 6 hours, within 5 hours, within 4 hours, within 3 hours, and within 1 hour. According to yet another aspect of the present disclosure, there is provided a method of administering a treatment plan to prevent or accelerate the reversal of diaphragmatic disuse atrophy in a patient receiving respiratory assistance from a ventilator. The ventilator provides a respiratory cycle to the patient, and the patient has a prescribed level of assistance. The method includes storing a measurement representing a preselected range of diaphragmatic output that is at least a portion of the prescribed level of assistance, monitoring the respiratory cycle of the ventilator, administering a stimulation signal to the patient in synchronization with the respiratory cycle of the ventilator to supplement to produce a certain level of diaphragmatic output in the patient's diaphragm, and adjusting the patient's diaphragmatic output due to the diaphragmatic supplementation for each stimulated respiratory cycle to fall within the preselected range of diaphragmatic output.

[0044] According to the 40th embodiment, the step of adjusting the patient's diaphragmatic output for each respiratory cycle includes monitoring the diaphragmatic output according to the last administered stimulation signal and comparing the diaphragmatic output of the last administered stimulation signal with the preselected range of diaphragmatic output.

[0045] According to the 41st embodiment, the step of monitoring the diaphragmatic output according to the last administered stimulation signal includes detecting diaphragmatic output data by one or more sensors and processing the detected diaphragmatic output data to determine the diaphragmatic output. In some embodiments, the diaphragmatic output includes one or more of parameters derived from air flow rate, tidal volume, pressure, and / or a combination of flow rate, tidal volume and / or pressure.

[0046] According to the 42nd embodiment, the step of adjusting the patient's diaphragmatic output for each respiratory cycle further includes comparing the determined diaphragmatic output with the preselected range of diaphragmatic output and modifying the stimulation signal to be administered with the next ventilator breath when the diaphragmatic output from the last administered stimulation signal is outside the preselected range of diaphragmatic output.

[0047] According to the 43rd embodiment, the step of modifying the stimulation signal includes increasing the intensity of the stimulation signal. According to the 44th embodiment, the step of increasing the intensity of the stimulation signal includes one or more of the steps of increasing the frequency of the stimulation signal pulse, increasing the amplitude of the stimulation signal pulse, and / or increasing the duration of the stimulation signal pulse.

[0048] According to the 45th embodiment, the diaphragm output includes tidal volume, pressure, or a combination thereof. According to yet another aspect of the present disclosure, a method for preventing diaphragmatic disuse atrophy in critically ill patients is provided. The method includes the steps of attaching a ventilator to the patient, monitoring the respiratory cycle of the ventilator, and within one of 12 hours or 6 hours while the patient is attached to the ventilator, administering a pre-programmed stimulation signal to the patient to recruit the patient's diaphragm to output a certain level of diaphragm output, and adjusting the level of the patient's diaphragm output for each respiratory cycle to match or exceed a pre-selected threshold based on the administration of the stimulation signal.

[0049] According to yet another aspect of the present disclosure, a method for constructing a treatment plan for a patient is provided. The treatment plan is intended to prevent disuse atrophy or restore the patient's diaphragm. The method includes the steps of evaluating the diaphragm for maximum diaphragm output and fatigue characteristics, and determining one or more stimulation signals that set the diaphragm output to a pre-selected percentage of the maximum diaphragm output.

[0050] According to the 46th embodiment, the method further includes the step of creating a stimulation administration plan that includes a series of individual stimulation signals, and the series of stimulation signals can vary in speed, duration, pulse width, frequency, and amplitude.

[0051] According to yet another aspect of the present disclosure, a method for evaluating the diaphragm is provided. The method includes monitoring data representing the flow rate and pressure of a ventilator breathing cycle, stimulating the diaphragm using a stimulation signal based on the monitored data of the ventilator breathing cycle, and determining one or more functional characteristics of the diaphragm from the response caused by stimulating the diaphragm using the stimulation signal. In some embodiments, the one or more functional characteristics include one or more of maximum static inspiratory pressure, inspiratory volume, work of breathing, pressure-time product, pressure-time index, EMG, maximum relaxation rate, and expiratory time constant.

[0052] According to yet another aspect of the present disclosure, a transvascular diaphragm pacing system for constructing a patient's treatment plan is provided. In some embodiments, this treatment plan prevents diaphragmatic disuse atrophy or restores the patient's diaphragm. The system includes at least one intravascular electrode configured to deliver a supplied stimulation signal. In some embodiments, this stimulation signal is configured to supplement the patient's phrenic nerve and has one or more stimulation parameters. The system also includes one or more sensors configured to detect a breathing cycle signal from an accompanying ventilator and a diaphragmatic response due to phrenic nerve supplementation, a pulse generator coupled to be electrically connected to the at least one intravascular electrode, and at least one input device configured to input data representing one or more aspects of the treatment plan. The system further includes a controller coupled to be electrically connected to the one or more sensors, the at least one input device, and the pulse generator. In some embodiments, this controller is programmed to evaluate the diaphragm for maximum diaphragm output and fatigue characteristics and determine one or more stimulation signals that set the diaphragm output to a preselected percentage of the maximum diaphragm output.

[0053] According to yet another aspect, a transvascular diaphragm pacing system for evaluating the diaphragm is provided. The system includes at least one intravascular electrode configured to deliver a supplied stimulation signal. The stimulation signal, in some embodiments, is configured to recruit the patient's phrenic nerve and has one or more stimulation parameters. The system also includes one or more sensors configured to detect a respiratory cycle signal from a ventilator and a diaphragmatic response due to phrenic nerve recruitment, a pulse generator coupled to be electrically connected to the at least one intravascular electrode, and at least one input device configured to input data representing one or more aspects of a treatment plan. The system further includes a controller coupled to be electrically connected to the one or more sensors, the at least one input device, and the pulse generator. The controller, in some embodiments, is programmed to monitor data representing the flow rate and pressure of the ventilator respiratory cycle, stimulate the diaphragm using a stimulation signal based on the monitored data of the ventilator respiratory cycle, and determine one or more functional characteristics of the diaphragm from the response caused by stimulating the diaphragm using the stimulation signal. In some embodiments, the one or more functional characteristics include one or more of maximum inspiratory static pressure, inspiratory volume, work of breathing, pressure-time product, pressure-time index, EMG, maximum relaxation rate, and expiratory time constant.

[0054] This summary is presented to introduce in a simplified form a selected number of concepts further described below in the "Detailed Description of the Invention." This summary is not intended to identify key features of the claimed subject matter nor is it intended to be used as an aid in defining the scope of the claimed subject matter.

[0055] Many of the above aspects, as well as the attendant advantages of the claimed subject matter, will be more readily understood when these are taken in conjunction with the following detailed description and the accompanying drawings.

Brief Description of the Drawings

[0056]

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DETAILED DESCRIPTION OF THE INVENTION

[0057] The following detailed description, in connection with the accompanying drawings in which like numerals refer to like elements, describes one of various embodiments of the disclosed subject matter and is not merely representative of the embodiments. Each embodiment described in this disclosure is provided merely as an example or illustration and should not be construed as preferred or advantageous over other embodiments. The illustrative examples provided herein are not exhaustive or limit the claimed subject matter to the precise forms disclosed.

[0058] In the following discussion, examples of a transvascular diaphragmatic pacing system (TDPS) and a method of delivering respiratory therapy to a patient are presented. In some examples of the TDPS, rapid insertion and placement of intravascular pacing electrodes are performed in critically ill patients who require intubation and invasive PPMV to support the physiological requirements of the human ventilatory system. In the examples described herein, the contractile properties of the diaphragm muscle are optimally utilized to prevent muscle disuse atrophy and muscle wasting. This can be accomplished by coupling the phrenic nerve using patterned functional electrical stimulation applied to an intravascular electrode that is temporarily and reversibly inserted into a central vein of the patient, such as the left subclavian vein and the superior vena cava. In some examples, the TDPS is designed to interface seamlessly with any commercially available positive pressure ventilation assist / support device, such as those commonly used in an intensive care unit (ICU) to treat critically ill patients with respiratory failure, pain, trauma, sepsis, or neurological disease or deficit.

[0059] Rapid insertion and placement of the disclosed system can be accomplished by using minimally invasive centerline catheter-based electrodes, such as those described in U.S. Patent Application No. 12 / 524,571, filed July 25, 2009. This electrode can be quickly attached to the patient under local anesthesia and activated rapidly, such that pacing therapy can be initiated within one or several hours of hospitalization / intubation. If indicated by the patient's clinical condition, pacing by electrical stimulation can continue in synchrony with ventilator breaths provided by substantially all makes or models of commercially available positive pressure ventilators operating in typical modes, such as control mode, assist mode, or adjunct mode. After treatment is completed, the pacing catheter electrode can be easily removed. In some embodiments, system pacing follows the operation of the ventilator, and in other embodiments, the ventilator initiates and / or assists the respiratory cycle based on physiological responses caused by the pacing system.

[0060] Rapid placement (i.e., within hours of admission / intubation) is advantageous for preventing the pathological effects of muscle disuse atrophy, which is known to occur very rapidly in patients who are mechanically ventilated and sedated, and for maintaining the strength and durability of the diaphragm muscle during periods when the patient cannot breathe independently. Figures 33A - C show examples of using TDPS to prevent diaphragmatic disuse atrophy or to restore the diaphragm to facilitate successful weaning from respiratory support. As a result, it is possible to achieve successful early weaning from the ventilator. Another advantage resulting from the functionality of the rapid placement of the systems described herein and the rapid initiation of diaphragmatic pacing therapy is that this intervention helps prevent / reduce the adverse effects of high airway / lung positive pressure (such as ventilator - induced lung injury (VILI)), which is a contributing factor to the high incidence of patients receiving mechanical ventilation who commonly encounter and are often unable to wean from mechanical ventilation and become long - term ventilator - dependent. Patients remaining on mechanical ventilation are at high risk of ventilator - associated pneumonia (VAP) and nosocomial (hospital - acquired) infections. Therefore, it is important that patients on mechanical ventilation be liberated (weaned) from mechanical ventilation as quickly as medically possible. The examples of pacing systems and methods described herein address this need and others.

[0061] As described in more detail below, the systems of the present disclosure are designed to stimulate the right phrenic nerve (to recruit the right - sided diaphragm), the left phrenic nerve (to recruit the left - sided diaphragm), or both phrenic nerves to recruit the entire diaphragm muscle. Additionally, each phrenic nerve can be recruited using a single stimulation channel per nerve or two or more stimulation channels. An example presenting one embodiment of using two stimulation channels per phrenic nerve is shown in FIG. 3. In some examples using two stimulation channels per nerve, stimulation pulses with a 180 - degree phase shift can be delivered.

[0062] In the following description, numerous specific details are set forth in order to provide a thorough understanding of one or more embodiments of the present disclosure. It will be apparent, however, to one of ordinary skill in the art that many embodiments of the present disclosure may be practiced without some or all of these specific details. In some instances, well-known methods, procedures, and components have not been described in detail so as not to obscure various aspects of the present disclosure. Further, it should be understood that any combination of the features described herein may be used in the embodiments of the present disclosure.

[0063] Referring now to FIG. 1, an example of a transvascular diaphragmatic pacing system, generally designated 20, constructed in accordance with aspects of the present disclosure is shown. As best shown in FIGS. 1 and 4, system 20 includes a stimulation device 24 coupled in electrical communication (e.g., wired or wireless) with one or more transvascular electrodes 28 adapted for placement within the body near the left and / or right phrenic nerve. In use, stimulation device 24 is configured to transmit a stimulation signal in the form of a stimulation pulse to one or more of electrodes 28. Electrodes 28 then emit the stimulation signal near the left and / or right phrenic nerve. Next, by stimulating the left and / or right phrenic nerve, it is intended to cause recruitment of the patient's diaphragm.

[0064] As will be described in more detail below, the parameters of the stimulation pulse (amplitude, duration, frequency, etc.) affect the amount of diaphragm recruitment and the resulting output (tidal volume, pressure, etc.). In that regard, and as will also be described in more detail below, a sensor 48 configured to sense various physiological parameters of the patient can, in part, display the diaphragmatic output and provide feedback to stimulation device 24 for control of the treatment being administered.

[0065] As described herein, system 20 can be the patient's only breathing assistance device. In another embodiment, system 20 operates in conjunction with a positive pressure mechanical ventilator 332 (the "ventilator 32") to meet the patient's breathing needs. In some embodiments, signals detected from a respiratory sensor 50 that monitors the breathing cycle of the ventilator 32 can be used to synchronize the delivery of the stimulation signal with the ventilator breathing cycle.

[0066] The patient's breathing needs may be referred to as the patient's defined assistance level. This defined assistance level is generally quantified as the tidal volume or pressure (or a combination of the two) supplied to the patient during one breathing cycle that meets the patient's minimum physiological function. Generally, the defined assistance level is approximately 7 - 10 mL per kg of the patient's body weight, converted to tidal volume. In some embodiments, the defined assistance level is met solely by artificial means (e.g., by system 20, by ventilator 32, or by a combination of the two). This can be done with a severely sedated and / or unconscious patient. In another embodiment, the defined assistance level can include some breathing effort initiated by the patient.

[0067] As will be described in more detail below, in some embodiments, a clinician, as part of a treatment plan, can program system 20 to meet the defined assistance level (i.e., the tidal volume, pressure, or both levels) by diaphragmatic recruitment. In another embodiment, the clinician can program system 20 to contribute by electrical recruitment of one or more phrenic nerves by a certain percentage value of the defined assistance level (amount, pressure, or both levels), herein referred to as the phrenic contribution or phrenic contribution level. This percentage can vary and is patient - dependent based on various factors such as the patient's physical condition, the disease afflicting the patient, and the elapsed time before any stimulatory treatment. In this embodiment, the remaining percentage of the defined assistance level can then be met by the ventilator 32, which the clinician can appropriately program at the start or during the application of the treatment plan.

[0068] In some embodiments, as described in more detail below, the system 20 performs one or more evaluations of a patient, for example, to determine the current state of the patient's diaphragm and to determine stimulation signal characteristics related to diaphragm recruitment such as threshold pulse width, pulse amplitude, pulse frequency, quasi-maximum pulse width, and supra-maximum pulse width. The threshold pulse width refers to the minimum pulse width at which there is a diaphragm response above that width. The threshold frequency refers to the lowest frequency at which partial or fully fused twitches occur above that frequency to generate effective diaphragm force and / or action.

[0069] Next, referring to FIG. 2, the placement of the electrodes 28 will be described with respect to the heart H and diaphragm D of the patient P. As shown in FIG. 2, the left and right phrenic nerves travel along the lateral and central sides of the heart and reach the diaphragm D. The left subclavian vein crosses near the left phrenic nerve and carries blood from the upper limb to the heart H. The superior vena cava crosses near the right phrenic nerve and carries deoxygenated blood from the upper body to the right atrium of the heart. As is known in the art, when the left or right phrenic nerve receives a sufficiently high electrical stimulation as voltage (V), current (mA), or charge (nanocoulomb), the phrenic nerve is activated and the diaphragm D contracts.

[0070] FIG. 3 illustrates one embodiment showing two channels of transvascular stimulation delivered to the left phrenic nerve by intravascular electrodes disposed within the left subclavian vein and two channels of transvascular stimulation delivered to the right phrenic nerve by intravascular electrodes disposed along the sidewall of the superior vena cava. Each phrenic nerve can be partially or fully recruited by a plurality of intravascular electrode combinations. Partial nerve recruitment from a plurality of intravascular electrode combinations is effective in reducing muscle fatigue over time.

[0071] Next, referring to FIG. 4, the components of the system will be described in detail. As shown in FIG. 4, system 20 includes a first electrode 28A having an anode electrode contact and a cathode electrode contact 30A, 32A disposed in the left subclavian vein and positioned in the vicinity of the left phrenic nerve. In the illustrated embodiment, a second electrode 28B having anode electrode contacts and cathode electrode contacts 30B, 32B can also be disposed in the left subclavian vein and positioned in the vicinity of the left phrenic nerve.

[0072] System 20 further includes a third electrode 28C having an anode electrode contact and a cathode electrode contact 30C, 32C disposed in the superior vena cava and positioned in the vicinity of the right phrenic nerve. In the illustrated embodiment, a fourth electrode 28D having anode electrode contacts and cathode electrode contacts 30D, 32D can also be disposed in the superior vena cava and positioned in the vicinity of the right phrenic nerve.

[0073] Although two electrodes are shown and described for stimulating each of the left and right phrenic nerves, it should be understood that other numbers of electrodes can be implemented with the embodiments of the present disclosure. For example, four electrodes can be used to stimulate each phrenic nerve. For further information regarding the placement of multiple electrodes within a blood vessel and the configuration of one type of electrode structure that can be implemented with the embodiments of the present disclosure, refer to U.S. Patent Application No. 12 / 524,571, filed Jul. 25, 2009. The disclosure of this application is hereby expressly incorporated herein by reference in its entirety. Additionally, while electrodes having anode electrode contacts and cathode electrode contacts are utilized to emit stimulation pulses into the phrenic nerve, other configurations are possible. For example, several cathode electrode contacts can be used in combination with a single anode electrode contact, and vice versa.

[0074] Each electrode 28 is electrically connected to a stimulation device 24. In the illustrated embodiment, each electrode 28 is electrically connected to the stimulation device 24 via a lead wire 40. System 20 further includes one or more sensors 48 configured to monitor a patient's response to phrenic nerve stimulation and / or other physiological characteristics. As will be described in more detail below, one or more sensors 48 can be part of a feedback control system for adjusting the stimulation applied to the patient. The plurality of sensors 48 can transmit data indicative of one or more of the following to the stimulation device 24: electromyogram activity (monitored intramuscularly, superficially, and / or intragastrically), central venous pressure (any particular component of this signal), heart rate, chest wall acceleration, blood oxygen saturation, carbon dioxide concentration, position / depth of an intravenous catheter, mechanical movement (i.e., from an accelerometer, length gauge, and / or strain gauge), resistance (i.e., from an impedance pneumograph and / or piezoresistive sensor), and / or other physiological or mechanical parameters. It should be understood that this information can be appropriately processed (e.g., filtered, conditioned, amplified, etc.) before being used by the stimulation device 24.

[0075] As used herein, the term "quantity" includes, but is not limited to, "inspired tidal volume," "expired tidal volume," or "minute ventilation volume." As used herein, the term "pressure" includes, but is not limited to, airway pressure, alveolar pressure, ventilator pressure, esophageal pressure, gastric pressure, transdiaphragmatic pressure, intrathoracic pressure, positive end-expiratory pressure, or intrapleural pressure. Any of the pressures can be a peak pressure, an average pressure, or a reference pressure. As used herein, the term "flow rate" includes, but is not limited to, inspiratory flow rate or expiratory flow rate.

[0076] In some embodiments, the electrodes 28 can also monitor a patient's physiological variables by virtue of their placement within the central vein. Such physiological variables that can be monitored can include, but are not limited to, central venous pressure, electrocardiogram, and mixed venous blood oxygen saturation. It should be understood that one or more sensors separate from the electrodes, such as one or more of the sensors 48, can be used to monitor such physiological variables.

[0077] In some embodiments, system 20 further includes, or alternatively, a respiratory sensor 50 for detecting parameters of the ventilator 32. In this regard, the respiratory sensor 50 can be configured to connect to any standard respiratory circuit used in intensive care ventilators, and thus the pacing system is not dependent on the brand of the ventilator used. Depending on its position within the respiratory circuit, the respiratory sensor 50 can monitor and / or measure several respiratory parameters and transmit such parameters to the stimulation device 24. As will be described in more detail below, the respiratory sensor 50 can be part of a feedback control system for adjusting the stimulation given to the patient or can be used alone as the feedback control system. The respiratory parameters to be detected can include, but are not limited to, air flow rate (inhaled and / or exhaled), volume, pressure (airway, esophageal, gastric, and / or any combination / derivative of the former). In some embodiments, another sensor can assist in obtaining one or more respiratory parameters.

[0078] In some embodiments, exemplary parameters are measured both going to and coming from the ventilator 32. In the illustrated embodiment, the respiratory sensor 50 is outside the ventilator 32, so the system is not dependent on the model of the ventilator. However, system 20 can also be integrated to use internal sensors of the ventilator that can provide information to system 20 for proper operation or to use signals supplied externally by the ventilator, such that the external respiratory sensor can be omitted.

[0079] The stimulation device 24 functions, in part, as a signal generator for performing diaphragm therapy in response to information received from one or more of sensors 48 and 50 and / or information programmed into system 20 by a clinician. In that regard, the stimulation device 24 sends pulses toward intravascular electrode 28 according to one or more of the protocols described herein. As will be described in more detail below, in some embodiments, this pulse has the property of delivering an appropriate charge to the phrenic nerve to effect a diaphragm recruitment sufficient to meet the selected diaphragm contribution of the aforementioned defined assist level (e.g., amount, pressure, both, or a derived parameter from amount and pressure).

[0080] For this purpose, the stimulation device 24 is configured to deliver a fully programmable stimulation including, but not limited to, the following: any number of pulses, any combination of defined pulses, any order of delivery of defined pulses, multiple instances of any defined pulse, any frequency of stimulation, and / or any delay between pulses (inter-pulse delay). Each pulse can be programmable separately (e.g., frequency, amplitude, duration, etc.). The stimulation pulses and / or trains may or may not generate a repeatable pattern.

[0081] Each pulse includes a charge injection phase and a charge balancing phase (biphasic). In some embodiments, as shown in FIG. 6, the duration and amplitude of the balancing phase are programmable as a ratio of the duration and amplitude of the charging phase such that zero net charge is maintained. This ratio is referred to as the charge:balance ratio (C:B ratio) and is applied such that the product of amplitude and duration (charge) is equal for both the charging and balancing phases. In some embodiments, each pulse is programmable by the following parameters: the ratio of charging duration to balancing duration, the pulse width range, the stimulation amplitude (current level), and the delay between the charging and balancing phases. The stimulation amplitude can be changed between the same phases (i.e., generating a current that gradually decreases with respect to the charging pulse width). Zero net charge is preferred, but non-zero net charge can also be used.

[0082] Since the diaphragm is skeletal muscle, pacing can be achieved by delivering one or more stimulation signals to cause mechanically effective contractions of the diaphragm. In this context, the stimulation signal can include a plurality of pulses grouped as a train of stimuli. As used herein, a train of stimuli is defined as a collection of stimulus pulses. This definition does not imply a particular configuration, order of delivery, and / or shape profile or envelope. FIGS. 7 and 8 show examples of trains of stimuli generated by the stimulation device 24 and delivered to stimulate the phrenic nerve toward the electrode 28. The train of stimuli can start with pairs (pairs of pulses) or triplets, which may be physiologically relevant. That is, as shown in FIG. 5, two or three consecutive pulses at the beginning of recruitment have been shown to raise the entire force profile by shifting the baseline upward at the first onset of recruitment. Similarly, pairs or triplets delivered midway through the train can cause a continuous increase in force. The upward shift in initial force generation means that the same amount of force can be generated from the diaphragm over a comparable period using fewer stimulus pulses. This can be highly advantageous. The reason is that overactivating the diaphragm with an excessive number of stimulus pulses can induce fatigue and can also cause a conversion from fast-twitch fibers (strong but fatigue-prone) to slow-twitch fibers (fatigue-resistant but unable to generate as much force).

[0083] A train of stimuli or pulses is typically characterized by rate, duration, pulse width, frequency, and signal amplitude. The rate of a train of stimuli corresponds to the number of trains of stimuli delivered per minute, which can be correlated with the patient's respiratory rate or the rate of a mechanical ventilator. The duration of a train of stimuli refers to the length of time the train of stimuli is delivered. The pulse width indicates the duration of each individual pulse making up the train of stimuli. Similarly, the frequency indicates the number of individual pulses delivered per second. Finally, the amplitude refers to the voltage of each pulse delivered. The parameters of amplitude, frequency, and pulse width determine the intensity of the induced diaphragmatic pacing.

[0084] In some embodiments, the stimulus trains form ramp trains. For example, a ramp train can be shaped by linearly increasing (or decreasing) either the instantaneous frequency of successive pulses within the train or the duration (pulse width) of successive pulses within the train, or both. A ramp train represents that the change in injected charge is induced by the programmed stimulus parameters and any applied modulation.

[0085] By varying the pulse width and frequency modulation, it becomes possible to design various ramp train envelopes. Referring to FIG. 9, it is possible to generate a ramp envelope of only the pulse width or only the frequency, or both the pulse width and frequency, during a single pacing ramp. The envelopes of the pulse width and the stimulation frequency can be modulated together, i.e., combined, during pacing to generate a desired ramp train as shown in the example of FIG. 10. For example, the combination AF results in a stepwise recruitment of the diaphragm motor neurons at a constant frequency (without rate coding), and the combination BA gradually recruits and derecruits the motor neurons with a gradually increasing rate coding, but any combination is possible. Also, by adjusting the relative ratio of the duration of the increase and decrease of the pulse width within a single pacing ramp, it is possible to change the rate (gradient) of recruitment and derecruitment of the motor neurons independent of rate coding. Further, the pulse width modulation and frequency modulation can be mathematically defined as piecewise functions of time, thereby making it possible to generate any desired ramp envelope while remaining within the scope of the present disclosure.

[0086] A number of sets of ramp trains can be generated, and there are some embodiments whose aim is to achieve one or more of the following by means of the ramp trains: 1) mimicking the physiological contraction of the diaphragm by using pulse width modulation and frequency modulation respectively to control recruitment and rate coding separately, 2) delaying the onset of motor neuron fatigue, 3) preserving the natural fiber composition of a healthy diaphragm, 4) conditioning the diaphragm to a specific fiber type, e.g., type 1 (slow contracting fibers, fatigue resistant).

[0087] Using various programmable stimulus sequences or ramp sequences, a clinician with the assistance of system 20, or with the help of system 20, can construct a treatment plan. To achieve various goals, the treatment plan constructed by the clinician depends on the patient. This treatment plan can include one or more of the following: the timing of pacing delivery associated with ventilator breathing (e.g., every breath, every other breath, every five breaths, etc.), intermittent stimulus segments (e.g., 15 minutes of stimulus delivery every hour), etc. As an example, in patients requiring PPMV and sedation, the treatment plan takes into account both major objectives of minimizing VIDD and minimizing the risk of VILI. As another example, in the treatment plan for a patient who can be awake for some part of the day, can breathe independently for several hours, and will soon attempt to wean, it is desirable not to pace while the patient is breathing spontaneously. Conversely, at night when the patient is again sedated and returned to PPMV, it may be desirable to pace at a low assist level to reduce the peak pressure required for breathing and reduce the risk of VILI.

[0088] In some embodiments, the treatment plan includes a function to skip stimuli, sometimes referred to as skip breathing, which allows for the delivery of ventilator breaths without stimuli from system 20. Additionally, or alternatively, the treatment plan can include sigh breaths. Sigh breaths can be characterized as intermittent programmable breaths that inject more charge (i.e., a stimulus sequence of greater magnitude) than normal breaths. As a result, a stronger diaphragmatic contraction occurs physiologically. Both characteristics can be programmably distinct and repeatable. For sigh breaths alone, the increased ratio of amplitude can be programmable based on the amplitude of a typical paced breath. These characteristics can be implemented separately or in combination.

[0089] Figures 13A - C show examples of skip breathing, sigh breathing, and a combination of skip breathing and sigh breathing, respectively. Figure 13A shows an example of skip breathing, where the system 20 skips every third breath. This means that during the skipped breaths, the patient receives full ventilatory support from the ventilator 32. During the skipped breaths, respiratory mechanisms such as tidal volume, lung compliance, airway resistance, or replenishment of lung regions may change. Figure 13B shows an example of sigh breathing generated by the system 20 while operating in synchrony with the ventilator 32. In this example, the sigh breath is given every third breath. Depending on whether the flow is controlled or the pressure is controlled, the sigh breath can change the respiratory mechanism. This characteristic mimics the characteristics of spontaneous breathing, i.e., variable tidal volume. Figure 13C shows an example of both skip breathing and sigh breathing that are periodically applied by the system 20.

[0090] The stimulation device 24 in some embodiments is configured to generate a constant - amplitude current pulse with a pulse duration controllable in 10 - microsecond increments in the range of 50 - 300 microseconds. The amplitude and duration of each pulse within a train are separately programmable. The amplitude of the pulse can be selected in 0.1 - mA increments between 0.1 and 10 mA. The main parameter that determines whether a stimulation pulse is sufficient to activate a nerve axon (reach its threshold and fire an action potential) is the charge delivered by the stimulation, where charge (in nC)=pulse - current amplitude (in mA)×pulse duration (in microseconds). In this context, the stimulation device 24 can generate pulses in the range of 5 nC to 3000 nC, and the charge per pulse can be specified in 1 - nC increments.

[0091] FIG. 4 shows a schematic view of one embodiment of the stimulation device 24. As shown in FIG. 4, the stimulation device 24 includes a controller 60 that receives signals detected from one or more sensors 48 and / or a respiratory sensor 50. The stimulation device 24 can also include a timer 64 and a power supply 68 coupled to the controller 60. The controller 60 is coupled to a pulse generation circuit 70 that sends a stimulation signal to one or more of the electrodes 28 via a lead wire 40. In one embodiment, the above-described components are coupled via a bus 72. In some embodiments, the power supply 68 of the stimulation device 24 includes one or more batteries. In another embodiment, the power supply 68 includes a power conditioner that receives power from a standard “main power supply” and converts it into appropriate power for the circuits of the stimulation device 24.

[0092] Those skilled in the art will understand that the controller 60 serves as the computing center of the stimulation device 24 for executing logic or by assisting in the execution of routines, instructions, etc. that give functions to the stimulation device 24. In that context, the logic, routines, instructions, etc. described herein can be implemented in the form of hardware, software, or a combination of hardware and software.

[0093] In some embodiments, the controller 60 includes one or more processors and memory. Logic, routines, instructions, etc. can include a set of control algorithms, such as resident program instructions and calibrations, stored, for example, in the memory and executed to obtain the desired functions of the system 20. These algorithms can be executed during a preset loop cycle such that each algorithm is executed at least once per loop cycle. Algorithms stored in a non - volatile storage medium are executed by the processor to: 1) monitor inputs from sensors 48, 50 and other data - transmitting devices, or poll these devices for data to be used by the processor, 2) generate one or more pulses to the pulse generator for delivery to the electrodes 28, and 3) adjust the patient's diaphragm output, among other functions. The loop cycle is executed at regular intervals during the ongoing operation of the system 20, for example, every 3.125 milliseconds, 6.25 milliseconds, 12.5 milliseconds, 25 milliseconds, and 100 milliseconds. Alternatively, the algorithms can also be executed in response to the occurrence of an event.

[0094] As used herein, the term processor is not limited to integrated circuits referred to as computers in the art, but broadly refers to, among other things, microcontrollers, microcomputers, microprocessors, programmable logic controllers, application - specific integrated circuits, other programmable circuits such as programmable gate arrays, and combinations thereof. In some embodiments, the controller 60 can include additional components including, but not limited to, a high - speed clock, analog - to - digital (A / D) and digital - to - analog (D / A) circuits, input / output circuits and devices (I / O), and appropriate signal - processing and buffer circuits.

[0095] It should be understood that the signals received from sensors 48 and 50 can be processed by an optional signal processing unit 80 before reaching the controller 60. For example, the signal processing unit 80 can include a dedicated circuit for receiving, processing, and filtering electrical signals detected by sensors associated with the patient and / or the ventilator 32, a processor such as a digital signal processor (DSP), and the like. The signal processing unit 80 can include amplifiers and circuits for processing, filtering, and / or amplifying the electrical signals supplied thereto. In some embodiments, the signal processing unit 80 performs separate tasks such as determining one or more physiological states. One physiological state that can be determined by the signal processing unit 80 is the patient's minute ventilation or tidal volume. Minute ventilation is a respiration-related parameter that measures the amount of air inhaled and exhaled during a specific period. Minute ventilation is the product of the respiratory rate and the tidal volume. The signal processing unit 80 can also be used to receive and process signals representing other respiratory activities such as intrathoracic pressure and chest wall movement. Of course, the determination of one or more physiological states, signal processing, logic, or steps can be performed by the controller 60 alone.

[0096] Referring still to FIG. 4, the stimulation device 24 includes one or more input devices 86. The input devices 86 can include switches, knobs, etc. held by the housing of the stimulation device and / or computer-like devices such as keyboards, touch pads, and the like. The input devices 86 can input data such as pacing parameters and ventilator parameters into the stimulation device 24. An output device 92 such as a monitor can also be provided.

[0097] In accordance with aspects of the present disclosure, one or more embodiments of system 20 can be operated in various pacing modes. The pacing modes can alternatively be used by a clinician according to the clinical condition of each patient and as needed, and also according to the operating characteristics of a ventilator, such as ventilator 32, that may be available in a particular ICU. The pacing modes can include, but are not limited to, a ventilator-initiated pacing mode, a pacer-initiated breathing mode, and an autonomous pacing mode. Those skilled in the art will understand that these modes can be engaged in many ways to produce various combinations of system functionality, but for the sake of brevity, not all possible combinations are listed herein. Next, each of these modes will be described in some detail.

[0098] The first mode of system 20 described herein is a ventilator-initiated pacing mode. As will be described in more detail below, in this mode, the stimulation device 24 is operated in synchronization with the operation of the ventilator 32. This mode can function as a control mode in which the flow rate or pressure is controlled by the ventilator and delivered at a predetermined frequency (respiratory rate), and can operate with any mechanical ventilator. The delivery of the stimulation ramp train generated by the stimulation device 24, such as any of those shown in FIGS. 9 and 10, can be synchronized with the ventilator 32 in several ways, some of which are shown in FIGS. 11 and 12. For example, the stimulation can begin at any time before, during, or after the start of the inspiratory phase of the ventilator 32, and / or can end at any time before, during, or after the end of the inspiratory phase of the ventilator 32.

[0099] Next, referring to FIG. 14, an example of a routine 100 configured to perform one or more functions of the system 20, including the ventilator-initiated pacing mode, is shown. As will be understood by those skilled in the art, the logic or routines described herein can represent one or more of any number of processing schemes, such as event-driven, interrupt-driven, multitasking, multithreading, etc. Accordingly, the various acts or functions illustrated can be performed in the order shown, in parallel, or omitted. Similarly, the order of processing is not necessarily required to achieve the functions and advantages, but is provided to simplify the illustration and description. Although not explicitly shown, one or more of the acts or functions shown can be performed repeatedly depending on the particular manner of use. Some of the functions performed by the routine can be combined or further divided into additional steps or acts.

[0100] As shown in FIG. 15, routine 100 begins at block 102 where the system is initialized. Initialization enables a clinician to program the system 20, for example, by entering various system parameters via the input device 86 according to a treatment plan. As described in detail above, the level of diaphragmatic contribution and the default assist level can be included in the treatment plan if they are not already known in the system 20 or cannot be derived from other data known in the system 20. In some embodiments, the level of diaphragmatic contribution can be entered as a percentage value of a defined assist level, or as a tidal volume, pressure, or both tidal volume and pressure, or as a parameter derived from tidal volume and pressure.

[0101] In some embodiments, a clinician can input the level of patient assistance prescribed according to the clinical condition. In some embodiments, the prescribed assistance level is programmed as a tidal volume. Alternatively, the prescribed assistance level can also be: (1) the amount of desired pressure generated by the diaphragm, (2) the product of pressure and volume, called the work of breathing (WOB) shown in FIG. 21, (3) the integral of pressure over time, called the pressure-time product (PTP), (4) an index derived from a monitored variable such as the pressure-time index (PTI), or (5) the reduction in airway pressure obtained by adding pacing to PPMV as compared to PPMV alone. The prescribed assistance level can be set while remaining within the scope of the claimed subject matter with respect to one of the aforementioned parameters or as a combination of one or more of these parameters.

[0102] Along with the diaphragm contribution level, the clinician can program the system 20 using one or more stimulation parameters such as amplitude, duration, frequency, etc. to supplement the diaphragm to meet the diaphragm contribution level (e.g., for volume or pressure, or both). In other embodiments, some of the stimulation parameters corresponding to the diaphragm contribution level may be pre-programmed in the system 20 or acquired by the system 20, as will be described in more detail below.

[0103] The clinician can also input the amount of treatment to be provided per 24 hours. For example, the clinician may want to provide treatment for only 8 hours out of 24 hours. The treatment can be administered continuously for 8 hours or divided into time - segmented blocks (e.g., 2 hours, 1 hour, 30 minutes, 15 minutes, etc.), which can be either fixed or variable. In the variable case, the time - segmented blocks can form a repeatable pattern as needed. The treatment can also vary the diaphragmatic contribution throughout the period of stimulation administration. In some embodiments, the clinician can program sigh breathing or skip breathing as described above with reference to FIGS. 13A - C. The clinician can further input one or more respiratory parameters such as the ventilator operation mode, respiratory cycle timing (i.e., breaths per minute). It should be understood that during the initialization phase that gives functionality to the system 20, the clinician can input other data.

[0104] Returning to FIG. 14, routine 100 proceeds to block 104 where the breathing cycle of the patient and / or the ventilator is monitored. In one embodiment, routine 100 executes a respiration detection algorithm that uses data from respiration sensor 50 to detect various phases of ventilator respiration or spontaneous respiration, such as the inhalation phase, inspiratory pause, exhalation phase, and expiratory pause. Further, the respiration detection algorithm can quantify various respiratory attributes, such as the duration of any of the above respiratory phases. The respiration detection algorithm can use any of the monitoring signals, such as flow rate, volume, or pressure, to evaluate a series of conditional expressions to identify and / or calculate the attributes of the breathing cycle. The method of identifying and / or calculating the attributes of the breathing cycle can include, but is not limited to, slope threshold detection, amplitude threshold detection, or a combination thereof. Further, the respiration detection algorithm can store and / or process waveform data of any combination of the current respiration or previous respirations. The respiration detection algorithm can also facilitate the operation of the system in an event prediction or event trigger manner. When detecting spontaneous respiration, the system can stop ongoing stimulation, or continue stimulation to increase spontaneous respiration or skip the next respiration.

[0105] Next, at block 106, synchronization is maintained between the ventilator 32 and the administration of pacing therapy. This ensures that diaphragmatic pacing by the stimulation signal emitted from the electrodes is synchronized with each respiration provided by the ventilator 32. If it is suspected that they are not coupled, pacing can be skipped and resumed immediately after the ventilation pattern stabilizes again. In another embodiment, pacing can continue while re - establishing synchrony. In some embodiments, synchrony can be determined by comparing the attributes of at least one previous breathing cycle (e.g., 12 breaths per minute) with the attributes of the current breathing cycle of the ventilator 32 determined by processing signals from respiration sensor 50 and / or one or more of sensors 48.

[0106] From block 106, the routine proceeds to block 108. At block 108, the diaphragm output (e.g., tidal volume, pressure, or a combination of the two) is adjusted so that the programmed prescription assistance level is surely met. In this context, in some embodiments, system 20 monitors data from one or more of sensors 48 and / or sensors 50 to determine the diaphragm contribution (tidal volume, pressure, or both) per ventilator breath. This diaphragm contribution can be calculated from the measured output of each ventilator breath (i.e., the sum of the diaphragm contribution and the ventilator contribution), or can be calculated directly from the sensor data. If the diaphragm output (or diaphragm contribution) due to the previously applied stimulus signal is within a preselected range, the programmed stimulus parameters are retained and continue to be used to generate the stimulus train for treatment administration in the next breath.

[0107] If the calculated diaphragm contribution obtained from the last applied stimulus signal differs from the target diaphragm contribution value by more than a preselected amount, the stimulus parameters can be modified to maintain the diaphragm output within the desired range (e.g., the amplitude and / or duration are increased). Such a difference between the calculated diaphragm contribution corresponding to the last applied stimulus signal and the programmed diaphragm contribution value can be viewed as a change in pressure (in volume-controlled mode / ventilator), or a change in tidal volume (in pressure-controlled mode / ventilator), or a change in any signal detected by one or more of sensors 48 or sensors 50. Next, the modified stimulus parameters are stored in memory. In some embodiments, system 20 operates in a "closed-loop" feedback manner, an example of which is shown in FIG. 15, to adjust the diaphragm output during operation of system 20.

[0108] In some embodiments, an assessment is made to clarify the reason for such a decrease in tidal volume or pressure. For example, in some embodiments, the difference in reaching the diaphragm contribution target may be due to the displacement of the stimulating electrode far from the optimal position. In another embodiment, the difference or variability in tidal volume or pressure between breaths can be due to the changing respiratory mechanism of the patient, or the time-dependent fatigue of the stronger force-generating and faster-fatiguing (type IIb) fibers.

[0109] Changes in the respiratory mechanism can include changes in airway resistance and / or changes in the compliance of the lung / chest wall. For example, in the embodiment shown in FIG. 16, the tidal volume is controlled during all breaths, corresponding to a ventilator operating in a volume control mode. If any change occurs in the resistance load or compliance load, this change is reflected as a change in airway pressure represented by the graph below the tidal volume. In the example of FIG. 16, the first two breaths show the baseline level of airway pressure when pacing the diaphragm in synchrony with the ventilator 32. In the third breath, the system encounters a compliance load, which can be inferred from the increase in peak airway pressure and the change in the gradient of the airway pressure waveform.

[0110] In the fourth breath shown in FIG. 16, the system 20 can examine the measured decrease in compliance and consider this to be due, for example, to a reduction in the force contribution of the faster-fatiguing type IIb fibers. By the fifth breath, the system 20 has adjusted its pacing parameters to restore the desired level (negative pressure) of diaphragm contribution to the entire ventilation assistance system, thereby returning the airway pressure to the prescribed assistance level.

[0111] It should be understood that the same principle can be applied to a pressure control type ventilator in which changes in the respiratory mechanism can be indicated by changes in tidal volume between breaths. The system 20 can be configured to adaptively modify the pacing parameters to return the tidal volume to the prescribed assistance level.

[0112] As described above, the differences or variability in tidal volume or pressure between breaths can also be due to the time-dependent fatigue of the stronger, faster-fatiguing (type IIb) fibers. For example, FIG. 17A shows the natural progressive decline in percentage of fast-fatiguing type IIb motor units contributing to force generation. Initially, type IIb motor units can generate much greater force than type I motor units, and their large-diameter axons are also the easiest to recruit by electrical stimulation. Thus, a low level of intensity of phrenic nerve stimulation is initially sufficient to produce the level of diaphragmatic contribution shown in FIG. 17B. As schematically shown in FIG. 18, initially only perhaps 15% of all motor units in the phrenic nerve need to be recruited by system 20 to match the prescribed force / pressure level of diaphragmatic contribution.

[0113] As shown in FIG. 17, type IIb motor units tend to fatigue over time and produce less force, thereby causing the force (diaphragmatic contribution) to drop below the programmed level of diaphragmatic contribution. To maintain diaphragmatic contribution, the intensity of stimulation can be gradually increased to recruit additional type 1 and type IIa motor units. As a result, the stimulation spreads over a larger cross-sectional area of the phrenic nerve (e.g., 30%), more type I and type II motor units are recruited, and the prescribed force is produced.

[0114] Force appears in the newly activated cross-section of the phrenic nerve of type IIb motor units and then drops again as they fatigue. At this point, the pacing intensity is increased again by the pacing control system to activate a larger cross-sectional area of the phrenic nerve, and more motor units are recruited to re-establish force output. This progressively increasing activation of the phrenic nerve continues and can ultimately recruit up to 100% of the phrenic nerve motor units. Finally, all type IIb motor units are knocked out by fatigue, and only type I and type IIa motor units continue to contribute to force.

[0115] It is to be understood that the increase in stimulation can be either a simple linear equation or a complex equation using the ratio of available fibers and the weight assigned to their fatigue resistance. The loss of force can be attributed specifically to the fatigue of the fast-fatiguing fibers using parameters such as the maximum relaxation rate and half-relaxation time. Changes in the slope of the first half of the diaphragm relaxation curve, which indicates the relative contribution of type I and type II fibers to force generation, can also be used. Other parameters specific to fatigue, such as the pressure-time index, expiratory time constant, EMG (and derived parameters such as any power spectrum thereof), and the ratio between the amplitudes of slow and fast contractions, can also be used to infer the changing state and determine the stimulus parameters to be modified.

[0116] In another embodiment, the closed-loop control scheme may include using doublets / triplets in response to the slowing of contractions associated with fatigue of the diaphragm motor units. When fatigue is detected in the system 20, the stimulation pattern is automatically changed to include doublets / triplets or otherwise lower the stimulation frequency. The reason is that this form of stimulation is known in the art to optimize force generation in fatigued / fatigued motor units. After the fatigued motor units have recovered their strength, the stimulation pattern can be changed back to a moderate stimulation frequency, with or without using doublets. This closed-loop scheme allows for continuous pacing of the diaphragm regardless of the onset or progression of fatigue, also reduces the number of stimulus pulses delivered, and protects the muscle from potential damage that can be caused by overstimulation.

[0117] Returning to FIG. 14, the stimulation therapy is administered at block 110. Administering the stimulation therapy includes generating a stimulation signal such as a stimulus or a ramp train. Depending on the result of block 108, the stimulation signal is generated by the original stimulation perimeter (is "perimeter" in the original text a misspelling of "parameter"? Stimulation "parameter"), or the stimulation parameters modified in block 108 described above. The delivery timing of the stimulation ramp train is also determined at block 110. For example, in this routine, the appropriate timing of phrenic nerve stimulation can be determined from the correlation with the actual respiratory cycle of the ventilator 32. Generally speaking, in the routine, the timing of stimulation is controlled according to a predefined rule based on parameter estimates from a respiratory detection algorithm or the like. The predefined rules can include whether the stimulation starts at any time before, during, or after the start of the inhalation phase of the ventilator 32, as shown in FIGS. 11 and 12, or whether the stimulation starts during the exhalation phase, as shown in FIG. 24.

[0118] For example, depending on the ventilator mode, the system 20 can cause a pressure signal or an air flow signal. After it is determined at block 104 or the like that the inhalation phase / exhalation phase stimulates during the inhalation phase, the stimulation train can be started by causing either the start of the exhalation phase followed by a delay, as shown in FIG. 23, or the start of the inhalation phase. By inducing the start of the exhalation phase, it is possible for the stimulation to occur before the start of the inhalation phase and maximize the diaphragmatic force during the inhalation phase. In addition, the stimulation during the exhalation phase can be realized by causing the start of the exhalation phase or the start of the inhalation phase with a delay, as shown in FIG. 24. It is preferable to use the start of inhalation or the start of exhalation, but conceivably, it is also possible to use the end of the inhalation / exhalation period. Furthermore, it is also possible to give a delayed stimulation so that the stimulation starts, for example, in the middle of the inhalation phase.

[0119] After the timing is determined, in the routine of block 110, the stimulation pulse is directed towards the stimulation electrode 28 and sent at an appropriate time for transfer therefrom. The routine returns to block 104 until the treatment period ends or the clinician stops the operation of the system 20.

[0120] In some embodiments, the system 20 can assist the clinician in determining the appropriate level of diaphragmatic contribution to be input into the system 20. In that context, the diaphragmatic contribution can depend on the state of the patient's diaphragm. For example, for a patient with a maximum diaphragmatic output of only 750 mL, if the clinician intends to target an assist level of 500 mL, the clinician may inadvertently select a diaphragmatic contribution level that requires sending the maximum stimulation charge, resulting in premature fatigue and the like. Considering the current state of the patient's diaphragm, the clinician may desire a much lower percentage selection so that the stimulation charge is between the threshold charge and the over-maximum charge.

[0121] Accordingly, in some embodiments, the state of the diaphragm and the respiratory system is first evaluated by the system 20 to appropriately select the diaphragmatic contribution level. In that context, the system 20 is configured to perform one or more evaluations of the patient's diaphragm and / or respiratory mechanism. This evaluation determines the maximum diaphragmatic output (volume, pressure, or both), as well as other parameters such as the fatigue characteristics, resistance, compliance of the diaphragm, and the relaxation characteristics of the respiratory system and its components. The evaluation can also be performed in synchronization with the ventilator 32 during or over the duration of the operation of the system 20. These tests can be performed by briefly disconnecting the patient from the ventilator 32 and pacing the diaphragm alone, or by using a series of pauses during the operation of the ventilator 32 (during which the diaphragm is paced alone) while the patient is connected to the ventilator 32. This series of pauses can be used manually by the clinician or can be automatically identified and used by the system 20 as natural pauses (end-inspiratory pause or end-expiratory pause) that are part of the normal ventilator breathing cycle.

[0122] Generally speaking, after the gas flow from the ventilator 32 is instantaneously blocked, the maximum static pressure generated by the diaphragm in response to over-maximally stimulating the phrenic nerve to induce a single contraction, an inclined contraction, or a strong contraction of the diaphragm is measured in the same manner as the diaphragm relaxation characteristics in the inhalation and exhalation phases. In this evaluation, the diaphragm can be paced alone with a preset duty cycle to evaluate the diaphragm function in terms of its strength and endurance characteristics. From the data detected by one or more sensors 48 and / or sensors 50, but not limited to only that, measured values and / or indices including the maximum static / dynamic inspiratory pressure, inspiratory volume, pressure-volume loop relationship, respiratory work, pressure-time integral, pressure-time index, EMG, maximum relaxation rate, and expiratory time constant can be derived. Diaphragm fatigue can be induced by continuous or intermittent stimulation of the phrenic nerve to evaluate the endurance limit and detect the presence of low-frequency and / or high-frequency fatigue. Since most normal values of the calculated or derived parameters have a wide normal range, a series of measurements at intervals over a time range from several minutes to several days can be performed on a patient by the pacing system to obtain a complete description of the evolving changes in the patient's diaphragm strength and endurance.

[0123] In some embodiments, a knowledge-based algorithm can be used to monitor the instantaneous data and / or trend data of the monitoring signal. Such instantaneous data and / or trend data, by its evaluation, makes it possible to predict the ease of patient weaning and / or weaning over time. Such a function can also be extended for clinicians to perform diaphragm evaluation tests in the ICU as a stand-alone screening tool and / or confirmation tool. The reason is that the transvascular pacing method of the diaphragm enables clinicians to evaluate the true state of the diaphragm without the confounding factors (such as reduced central vitality) usually associated with spontaneous breathing techniques.

[0124] After the maximum diaphragm output is determined, the diaphragm contribution level can be selected using knowledge of the relationship between the prescribed assist level and the maximum diaphragm output. To understand this relationship, in some embodiments, controller 60 can recursively estimate, by one or more subroutines, the percentage value of the maximum diaphragm output required to generate 100% of the prescribed assist level. Of course, this calculation and other calculations can be performed and imported on a separate computer system or, alternatively, can be input to controller 60 prior to operating system 20. An example of this recursive estimation is shown in FIG. 19.

[0125] In some embodiments, and generally as described above, the clinician has the option to adjust the diaphragm contribution during operation of system 20, as indicated by the dial of FIG. 20, from 0 to 100% of the prescribed assist level, depending on the patient's condition and treatment goals.

[0126] Figure 20A shows an example of setting the desired diaphragm contribution to 75% of the prescribed assist level (i.e., the target diaphragm contribution level). In this example, the remaining 25% of the ventilation work is performed by the ventilator 32. Thus, the clinician can adjust the ventilator settings to contribute 25% of the ventilation work as tidal volume or pressure assist, as shown in the lower graph of Figure 20A. Figure 20B shows another example of setting the desired diaphragm contribution to only 25% of the prescribed assist level (i.e., the target diaphragm contribution level). In this example, the remaining 75% of the ventilation work is performed by the ventilator 32. Thus, the clinician can adjust the ventilator settings to contribute 75% of the ventilation work as tidal volume or pressure assist, as shown in the lower graph of Figure 20B. Alternatively, PPMV can be set to a mode in which the remaining portion of the prescribed assist level is automatically determined and adjusted by the ventilator during the inter - breath or within the breath (e.g., pressure - regulated volume - control mode). In some embodiments, the system 20 can also calculate or otherwise obtain the stimulation characteristics corresponding to the diaphragm contribution. In another embodiment, the clinician can input data representing these stimulation characteristics.

[0127] In some embodiments, the state of the diaphragm is periodically re - evaluated after a period of treatment (e.g., 12 hours, 1 day, etc.) is administered. For example, as briefly described above with respect to the closed - loop control method for adjusting diaphragm output, in some cases the variability in volume or pressure during the inter - breath can be due to the changing patient respiratory mechanics, including changes in airway resistance and / or changes in lung / chest wall compliance. In another embodiment, the diaphragm muscle has been strengthened by the administration of treatment, and thus the diaphragm contribution can be increased, or the intensity of the stimulation can be reduced to adjust the diaphragm contribution. In these cases, it may be beneficial to periodically re - evaluate the diaphragm after treatment has been initiated and optimize the pacing treatment accordingly.

[0128] An example of a routine for measuring changes in the diaphragm state without transferring the patient from the ventilator 32 is shown in FIG. 22. Similar to the above-described diaphragm evaluation, in some embodiments, a series of approximation routines can be used to determine the optimal parameters of the stimulus for the patient.

[0129] As best shown in FIG. 22, routine 200 begins with the clinician providing initial system parameters that may include maximum allowable stimulus parameters. The stimulus parameters can be provided as a pre-specified stimulus train with a fixed duration such that the stimulus train is fully defined by the user using the methods described above, or as a stimulus train based on the number of pulses and train duration detected based on the ventilator inhalation time. Next, in this routine, a respiration detection algorithm is executed to detect the inhalation and exhalation phases using the flow / pressure data detected by the respiration sensor 50. In addition, data on the flow and pressure for one or more breaths without using a stimulus are collected and stored.

[0130] Depending on the ventilator mode, system 20 can cause a pressure signal or an air flow signal. After it is determined that the inhalation / exhalation phase will stimulate during the inhalation phase, the stimulus train can be initiated by causing either the start of the exhalation phase followed by a delay, as shown in FIG. 23, or the start of the inhalation phase. By inducing the start of the exhalation phase, it is possible for the stimulus to occur before the start of the inhalation phase and maximize the diaphragmatic force during the inhalation phase. In addition, the stimulus during the exhalation phase can be achieved by causing the start of the exhalation phase, or the start of the inhalation phase with a delay, as shown in FIG. 24. It is preferred to use the start of inhalation and the start of exhalation, but where possible, it is also possible to use the end of the inhalation / exhalation period. Furthermore, it is also possible to provide a delayed stimulus such that the stimulus starts, for example, in the middle of the inhalation phase.

[0131] Data on the flow rate, volume, and / or pressure for at least one breath using the stimulus, or derived parameters thereof, are recorded. If information on multiple breaths is recorded for data with and without the use of the stimulus, the data can be averaged together. Next, the flow rate / volume / pressure data collected using the stimulus are subtracted from the flow rate / volume / pressure data collected without using the stimulus. This difference, calculated as an area (and illustrated as the blackened area), can be used as a relative measure of the force generated by the diaphragm, as shown in FIG. 26. In the case of pressure-controlled ventilation, the volume difference (the area under the flow curve) is used as the measured value. In the case of volume-controlled ventilators, the area under the pressure graph is used as the measured value.

[0132] FIG. 27 is an example of another evaluation routine 300 executed by the system 20. The evaluation routine 300 can be used to guide intravascular electrode placement during normal ventilator operation (i.e., without interference with ventilator operation or disconnection of the ventilator), and can evaluate diaphragmatic recruitment in response to changing (decreasing or increasing) stimulus charges. When the evaluation routine 300 is executed, the system 20 can apply a low-frequency stimulus (such as from 1 Hz to 5 Hz) during one or more end-expiratory periods to induce an unfused diaphragmatic contractile response in the form of a single twitch. The charge delivered can be increased progressively to construct a complete neural recruitment curve for each intravascular location, and the operator can define how many respiratory cycles this stimulus is delivered over. The system 20 can analyze this stimulus and response information to algorithmically estimate the best electrode position for stimulating one or both phrenic nerves using the least amount of charge (highest efficiency). During this evaluation routine, the system 20 can also collect information including diaphragmatic output (volume, pressure, or both) regarding the relationship between the stimulus train characteristics and the corresponding diaphragmatic response. Some of the stimulus parameters that can be obtained include, but are not limited to, the threshold pulse width and supramaximal pulse width required to recruit each phrenic nerve from an appropriate intravascular electrode position.

[0133] As illustrated in FIG. 28, the stimulus charge of routine 300 can be programmed to occur periodically during the baseline flow / volume period, which can occur during the end-expiratory pause, sometimes referred to as the end-expiratory delay, of the ventilator respiratory cycle. The advantage of selective stimulation during the end-expiratory pause is that the length of the diaphragm muscle fibers is the same before each stimulus is delivered, thereby establishing a standardized state for obtaining comparable results. This results in a standardized baseline for comparing diaphragmatic twitch responses and can guide intravascular electrode placement.

[0134] This zero-volume period can be determined prior to stimulation to determine the duration of the end-expiratory pause. In this regard, FIG. 29 shows an example of routine 400 for determining the duration of the end-expiratory pause. With this routine, flow data is collected and the end-expiratory pause is estimated. In some embodiments, the inspiratory and expiratory volumes are calculated. The point at which the exhaled volume reaches the user-programmable percentage of the inspiratory volume can be used as the start time of the end-expiratory pause. In one embodiment, the percentage used as the default value is 85% of the volume inhaled. In some embodiments, volume is used because it is less affected by noise than other metrics.

[0135] Using volume data in some embodiments is one technique, but this does not exclude using other metrics of the end-expiratory phase, such as a slope close to zero, or simply using a fixed time interval at the end of the expiratory phase as the end-expiratory pause. In another embodiment, system 20 can calculate relaxation characteristics of the respiratory system, such as the expiratory time constant (i.e., the time required to exhale a specific percentage of the air from the lungs), to determine the ideal end-expiratory pause duration and prompt the clinician to adjust the ventilator settings accordingly. At any point in the evaluation, the user has the ability to disable the system manually and to select the percentage value of the measured expiratory duration or the duration of the end-expiratory pause as an absolute value.

[0136] Returning to FIG. 27, evaluation routine 300 will be described in some detail. Routine 300 begins at block 302 where a clinician provides initial system parameters or accepts internal default values, which may include characteristics of a low-level start stimulation signal, a maximum stimulation level, an estimated duration of end-expiratory pause, one or more ventilator parameters, and the like. In some embodiments, the characteristics of the low-level start stimulation signal are based on the estimated duration of end-expiratory pause.

[0137] Next, at block 304, the breathing detection algorithm described above can be used to synchronize the applied stimulation with the end-expiratory pause period of ventilator 32. For example, as shown in FIG. 28, the breathing detection algorithm can be used to identify the period of interest during the breathing cycle in which stimulation can be delivered. Since the diaphragm is a skeletal muscle, its force output varies with its length as shown by its length-tension relationship. Therefore, it is beneficial to stimulate the diaphragm at approximately its resting length, thereby obtaining a standard baseline for comparing single twitch responses of the diaphragm. The resting length of the diaphragm is reached at the end of every expiratory phase when the lungs reach their functional residual capacity. Therefore, the inspiratory and expiratory volumes can be monitored to non-invasively estimate when the lungs reach their functional residual capacity. In addition, signals such as pressure signals in the form of esophageal or intrathoracic pressure from one or more of sensors 48 and / or from sensor 50 can be used to confirm that the lungs have reached their functional residual capacity.

[0138] At block 306, based on the monitoring parameters described above, a determination is made as to whether the patient's lungs have returned to their functional residual capacity when the ventilator executes a breathing cycle. If it is determined that the functional residual capacity has been reached, system 20 provides a start stimulation signal at block 308 and then monitors and measures the diaphragmatic response to the applied stimulation at block 310. Signals that can be monitored and measured to quantify the diaphragmatic response can include, but are not limited to, EMG, airway pressure, airway flow, intrathoracic pressure, intrapleural pressure, central venous pressure, thoracoabdominal movement, various patient impedances, and the like.

[0139] Next, at block 312, a determination is made as to whether the next ventilator breath is about to begin. The estimated expiratory end pause duration and / or the monitoring signals from sensors 48, 50 may assist in this determination. If not, routine 300 increases the strength of the stimulation at block 314, returns to block 308, and delivers a pulse of increased strength. If the next ventilator breath is about to begin, the stimulation for the current breath is stopped at block 316, the strength of the current stimulation level can be increased at block 318, and the routine returns to block 304 to deliver another stimulation in synchronization with the respiratory cycle. Routine 300 can continue to loop in some embodiments until a pre-set range of stimulation intensity is reached or until the maximum stimulation level is reached.

[0140] Since the functional residual capacity can change over time due to factors such as extrinsic positive end-expiratory pressure (PEEP) or intrinsic positive end-expiratory pressure, the system can also use a validity check to confirm that the functional residual capacity (and thus the diaphragmatic rest length) has not changed between breaths. One means of performing this validity check is to analyze the trend data of the end-expiratory volume before stimulating the diaphragm.

[0141] The following modes of operation that can be implemented in the embodiment of the system 20 include a pacer-initiated breathing mode. FIG. 30 shows an example of a routine 500 that is executed by the system 20 to implement one or more functions including the pacer-initiated breathing mode. In that context, many mechanical ventilators have an assist / support mode in which ventilation occurs when the patient attempts to breathe on their own. In this embodiment, as shown in FIG. 31, the system 20 can trigger the ventilator 32 operating in the assist mode by using the stimulus (and the resulting response from the diaphragm) indicated by "D" in FIG. 31 and program it to mimic the patient's spontaneous effort. The ventilator 32 responds to this trigger signal / event and delivers breaths to the patient (based on parameters set by the clinician) indicated by "B" in FIG. 31. In practice, the system 20 drives the breath delivery from the ventilator 32 indicated by "C" in FIG. 31 (opposite to the aforementioned ventilator-initiated pacing mode). In some embodiments, the system 20 does not perform breath detection and thus the breath sensor 50 can be omitted. In some embodiments, the breath sensor 50 can be used to perform various evaluation routines and feedback schemes. The system 20 can control the pacing rate by programmable parameters such as the respiratory rate (breaths per minute), skipped breaths, and sigh breaths. Similarly, the pacer-initiated breathing mode can also include one or more of an adaptive function, closed-loop control, and diaphragm evaluation, and the series of approximation functions described above for the ventilator-initiated pacing mode are also applicable to this mode.

[0142] In the pacer-initiated breathing mode, the system 20 can use feedback to ensure an appropriate diaphragm contribution. Some ventilator modes suitable for this embodiment include pressure support ventilation (PSV), pressure-regulated volume control (PRVC), proportional assist ventilation (PAV), and adaptive support ventilation (ASV).

[0143] Embodiments of the system 20 can also be operated in an autonomous mode, i.e., mode A. Mode A is a life support mode that can operate independently of the ventilator 32. FIG. 32 shows an example of a routine 600 executed by the system 20 to perform one or more functions including the autonomous mode. In this context, mode A operates in closed-loop control using feedback from various sensors such as one or more of the sensors 48, 50. These sensors can be used to monitor physiological variables including, but not limited to, central venous pressure, mixed venous oxygen saturation, heart rate, and level of motor activity. In mode A, adjustable diaphragmatic pacing is performed for patients who have no, some, or all of their maintained spontaneous breaths and require assisted breathing, and can automatically adapt to the patient's physiological needs and changing activity levels as needed.

[0144] Mode A can be a life support mode, but this mode may or may not be used with this capability (i.e., it can also be connected to a backup ventilator). For example, mode A may be applicable to patients who are permanently dependent on a mechanical ventilator or, alternatively, patients who require continuous pacing from the system 20.

[0145] In contrast to the aforementioned embodiments of the system 20 for implementing the pacer-initiated respiratory mode and the ventilator-initiated pacing mode, embodiments of the system 20 for implementing mode A can be fully implanted under the skin of the patient's upper chest. In this context, the system 20 is powered from a power storage source such as a primary battery or a rechargeable implantable battery and can be integrated with other implantable devices that assist the patient's heart or other functions.

[0146] As shown in the embodiment of FIG. 32, system 20 operating in A mode includes a closed-loop operation for autonomously pacing the diaphragm. In this mode, any patient response signals (feedback) that assist in indicating the need for pacing can be utilized, and these signals include, but are not limited to, oxygen saturation, end-tidal CO2 (EtCO2), air flow, heart rate, signals from a motion detection accelerometer, and the like. An algorithm is used to detect and / or modify the physiological response signals to determine whether changes in the stimulation pattern, frequency, respiratory rate, intensity, type, and / or shape characteristics are required for the pacing to continue to be applied in A mode and induce the expected response.

[0147] The principles, representative embodiments, and modes of operation of the present disclosure have been described thus far. However, the aspects of the present disclosure that are to be protected should not be construed as being limited to the specific embodiments disclosed. Further, the embodiments described herein should be regarded as illustrative rather than limiting. It should be understood that modifications and changes may be made by others without departing from the spirit of the present disclosure, and equivalents may be used. Accordingly, it is clear that all such modifications, changes, and equivalents fall within the spirit and scope of the present disclosure as claimed.

Claims

1. In a stimulation system, a stimulation device for stimulating the phrenic nerve with a stimulation signal during one breath of a patient; a sensor for acquiring diaphragm output data; an electronic storage device storing instructions for controlling the stimulation system; a processor, receiving the diaphragm output data from the sensor; processing the diaphragm output data to determine the amount of work of breathing performed by the patient's diaphragm; determining that the amount of work of breathing is outside a selected range; and changing the stimulation signal in response to the amount of work of breathing being outside the selected range, the stimulation system comprising the processor for executing instructions to perform the steps.

2. The stimulation system according to claim 1, wherein the stimulation device stimulates the phrenic nerve by delivering the stimulation signal to a plurality of electrodes supported on a catheter.

3. The stimulation system according to claim 2, wherein the plurality of electrodes includes a first group of electrodes disposed proximate to the left phrenic nerve and a second group of electrodes disposed proximate to the right phrenic nerve.

4. The stimulation system according to claim 1, wherein the breathing is the breathing while the patient is receiving breathing assistance from a ventilator.

5. The stimulation system according to claim 1, wherein the processor further executes instructions for acquiring an attribute of the patient's breathing cycle.

6. The stimulation system according to claim 1, wherein the processor further executes instructions for determining a timing for stimulating the phrenic nerve in relation to the patient's breathing cycle.

7. The stimulation system according to claim 1, wherein the amount of work of breathing includes the amount of work performed by the patient during one or more phases of one breathing cycle.

8. The stimulation system according to claim 1, wherein the amount of work of breathing includes the amount of work performed by the patient's diaphragm.

9. The stimulation system according to claim 1, wherein the sensor acquires the diaphragm output data by sensing an air flow generated by the patient.

10. The stimulation system acquires diaphragm output data for a plurality of breaths performed by the patient using the sensor; averages the diaphragm output data to generate averaged diaphragm output data; and The stimulation system according to claim 1, wherein the work of breathing is determined by determining an average of the work of breathing performed over the plurality of breaths based on the averaged diaphragm output data. **Claim 11** The stimulation system according to claim 1, wherein the diaphragm output data includes airway pressure and tidal volume. **Claim 12** The stimulation system according to claim 11, wherein the work of breathing includes the product of airway pressure and tidal volume.

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