Transvascular diaphragmatic pacing system and method 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 diaphragmatic pacing system and a method for its use. [Background technology]

[0002] Patients in hospital intensive care units (ICUs) may have an underlying medical condition that reduces their ability to breathe voluntarily and require positive pressure mechanical ventilation (PPMV) to provide ventilatory support. PPMV is routinely used in the ICU in conjunction with administration of sedatives to provide artificial ventilation for these critically ill individuals. In addition, many patients undergoing surgery under general anesthesia, for example in a hospital operating room (OR), or procedures under anesthesia or sedation, for example in a hospital emergency room (ER), typically require PPMV for ventilatory support while they are anesthetized or sedated.

[0003] Mechanical ventilation is a life-sustaining method, but when combined with sedation or anesthesia, it prevents active contraction of the diaphragm. Prolonged, fully controlled mechanical ventilation can completely abolish neural and mechanical activation of the diaphragm and has been shown to induce muscle atrophy, protein degradation, and reactive oxygen species release, leading to rapid loss of diaphragm function, a syndrome known as ventilator-induced diaphragm dysfunction (VIDD).

[0004] The onset of diaphragmatic disuse atrophy is rapid and leads to slower patient recovery, resulting in increased ventilator dependence and higher incidence of ventilator-associated pneumonia and hospital-acquired infections, longer ICU stays, and increased hospital costs.

[0005] In addition to ICU patients, mechanical ventilation is the primary form of ventilatory support for individuals with medical conditions such as spinal cord injury (SCI) that adversely affect neurological function. These patients may have a reduced ability to breathe voluntarily due to partial or complete loss of diaphragm control, predisposing them to lifelong dependence on mechanical ventilators.

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

[0007] The two phrenic nerves that control the activation of the diaphragm run along the left and right sides of the heart through the chest to the diaphragm. Phrenic nerve stimulation is performed by electrically stimulating the phrenic nerve that controls the patient's diaphragm, which can trigger a respiratory cycle. Traditional techniques include implanting a nerve cuff around the phrenic nerve (at neck or chest level) 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 expensive, so it is only used selectively for patients who require lifelong assisted breathing. In addition, placing the nerve cuff directly around the phrenic nerve can damage the phrenic nerve. These phrenic nerve stimulation systems have not previously been prescribed for temporary use in critically ill ICU patients.

[0008] Other phrenic nerve stimulation techniques are known (such as that described in U.S. Patent No. 5,393,633). However, the system disclosed in U.S. Patent No. 5,393,633 does not allow for acute short-term use in an ICU environment for the management of ICU patients, especially in the first few days after initiation of PPMV.

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

[0010] One such diaphragmatic pacing system is described in U.S. Pat. No. 6,399,436. In addition to being surgically laborious, the diaphragmatic pacing system of U.S. Pat. No. 6,399,436 is used to treat type IIa (fast) muscle fibers to type I (delayed) muscle fibers in patients who have been mechanically ventilated for long periods of time and have all of their muscle fibers atrophy and convert to the fast type (VIDD). However, the treatment described in U.S. Pat. No. 6,399,436 is not desirable for treating critical care patients who still have both type IIa (fast) and type I (delayed) muscle fibers, and both types need to be successfully weaned off PPMV. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 8,195,297 [Patent Document 2] U.S. Patent No. 7,962,215 Summary of the Invention [Problem to be solved by the invention]

[0012] Thus, a need exists for minimally invasive diaphragmatic pacing systems and methods for appropriate use in the ICU environment, particularly for acute short-term use for the management of ICU patients in the days or weeks following initiation of PPMV. [Means for solving the problem]

[0013] The example systems and methods disclosed herein address this need and others by providing a minimally invasive neurostimulation system that transvascularly paces the phrenic nerve via disposable intravascular electrodes that can be placed percutaneously under local anesthesia. As described in the Detailed Description, such pacing systems and methods can be used to provide short-term electrical stimulation to prevent disuse atrophy of the diaphragm in patients at risk of becoming ventilator dependent and / or to reverse disuse atrophy of the diaphragm in ventilator dependent patients.

[0014] The system is designed to operate in conjunction with a mechanical ventilator to produce diaphragmatic contractions synchronized with each ventilator-delivered breath and intermittently synchronized with some ventilator breaths, or to operate as a stand-alone system. In some embodiments, the system and method can be used for just a few minutes or hours after the patient's initial intubation. Such diaphragm pacing therapy is expected to prevent, reduce or reverse diaphragm disuse atrophy that typically occurs in patients on PPMV or those expected to require PPMV and sedation for extended periods of time, and further avoid or reduce adverse effects associated with PPMV. As a result, patients can be successfully weaned off PPMV sooner than currently known methods, resulting in a significant reduction in total hospitalized patient costs, not to mention significant health benefits for the patient.

[0015] According to one aspect of the present disclosure, a method is provided for administering a treatment regimen designed to prevent or reverse diaphragm disuse atrophy in a patient receiving respiratory assistance from a ventilator. The ventilator is used to deliver breathing cycles to the patient having a prescribed level of assistance. The method includes monitoring the breathing cycles of the ventilator, delivering a preprogrammed stimulation signal to the patient to assist the patient's phrenic nerve, and modulating the patient's diaphragm output for each breathing cycle. In some embodiments, the stimulation signal is delivered via one or more intravascular electrodes.

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

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

[0018] According to a third embodiment, the one or more ventilator breath parameters include timing data representative of the duration of a ventilated breath. According to a fourth embodiment, the method also includes maintaining synchrony between delivery of the stimulation signal and the ventilator breathing cycle.

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

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

[0021] According to an eighth embodiment, the stimulation signal includes stimulation signal characteristics that result in meeting a diaphragm contribution level when the stimulation signal is delivered to a patient. According to a ninth embodiment, the diaphragm contribution level is measured for tidal volume or pressure separately, together and including their components.

[0022] According to a tenth embodiment, the prescribed diaphragm contribution level depends on the patient's medical condition and the contractile ability and / or functional state of the diaphragm. According to an eleventh embodiment, determining the contractile capacity includes testing stimulation patterns to measure strength and endurance from diaphragmatic responses.

[0023] According to a twelfth embodiment, the patient's medical condition and the contractile ability of the diaphragm and / or the functional status of the phrenic nerve are assessed prior to administration of the treatment regimen and / or during administration of the treatment regimen. According to a thirteenth embodiment, determining the strength and durability of the patient's diaphragm includes measuring the maximum diaphragmatic output and fatigue characteristics of the diaphragm.

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

[0025] According to a fifteenth embodiment, monitoring the respiratory cycle further includes determining at least one of the amplitude and rate of change of the ventilator output signal on a breath-by-breath basis. According to a sixteenth embodiment, administering the stimulation signal includes generating the stimulation signal in response to one or more pacing parameters and delivering the stimulation signal in association with a ventilator breathing cycle.

[0026] According to a seventeenth embodiment, adjusting the patient's diaphragm output for each respiratory cycle, such as a paced respiratory cycle, includes monitoring the diaphragm output in response to the last administered stimulation signal and comparing the diaphragm output of the last administered stimulation signal to a preset target range. Alternatively, the method can skip pacing for one respiratory cycle (MV only) but stimulate in the next respiratory cycle (i.e. mechanical ventilation and diaphragm pacing). The method can then compare both of these values ​​and adjust the next paced breath.

[0027] According to an eighteenth embodiment, monitoring diaphragm output in response to the most recently administered stimulation signal includes sensing, by one or more sensors, diaphragm output data representative of one or more of airflow, tidal volume, pressure, and / or parameters derived from a combination of flow, tidal volume and / or pressure, and processing the sensed diaphragm data to determine diaphragm output.

[0028] According to a nineteenth embodiment, adjusting the patient's diaphragmatic output for each respiratory cycle further includes modifying the stimulation signal to be administered with the next ventilator breath if the diaphragmatic output of the last administered stimulation signal is outside a preselected target range.

[0029] According to a twentieth embodiment, the preselected target range includes a diaphragm contribution level. According to a twenty-first embodiment, the method further comprises determining if the diaphragm output of the last administered stimulation signal is outside of a preselected target range.

[0030] According to a twenty-second embodiment, if the cause is due to a change in the patient's respiratory mechanics, the condition of the patient's diaphragm and respiratory system is evaluated during administration of the treatment plan. According to a twenty-third embodiment, the method further includes reprogramming the stimulation signal based on the assessed diaphragm state.

[0031] According to a twenty-fourth embodiment, evaluating the diaphragm includes monitoring data representative of flow and pressure of the ventilator breathing cycle to determine timing of end-expiratory delay, progressively stimulating the diaphragm with 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, the one or more functional characteristics including one or more of maximum static inspiratory pressure, inspiratory volume, work of breathing, pressure-time product, pressure-time index, electromyogram (EMG), maximum relaxation rate, and expiratory time constant.

[0032] According to a twenty-fifth embodiment, diaphragmatic stimulation is targeted to occur during each ventilator breath to reduce positive pressure and reduce the risk of ventilator-induced lung injury (VILI). According to a twenty-sixth embodiment, monitoring the breathing cycle of the ventilator includes detecting signals representative of inhalation and exhalation of the ventilator and calculating one or more of an inhalation phase, an exhalation phase, an inhalation pause, and an exhalation pause.

[0033] According to a twenty-seventh embodiment, the step of administering the stimulation signal includes delivering the stimulation signal simultaneously with the inspiration phase. According to another aspect of the present disclosure, a transvascular diaphragm pacing system is provided for preventing or reversing diaphragm disuse atrophy in a patient receiving respiratory assistance from a ventilator. The system includes at least one intravascular electrode configured to deliver a delivered stimulation signal. The stimulation signal is configured in some embodiments to assist the patient's phrenic nerve, the stimulation signal having one or more stimulation parameters in some embodiments. The system also includes one or more sensors configured to sense an associated respiratory cycle signal from the ventilator and a diaphragm response due to phrenic nerve assistance, a pulse generator coupled in electrical communication with the at least one intravascular electrode, and at least one input device configured to input data representative of one or more aspects of a treatment plan. The system further includes a controller coupled in electrical communication with the one or more sensors, the at least one input device, and the pulse generator. The controller, in some embodiments, is programmed to receive input data representative of one or more aspects of the treatment plan, including sensed signals representative of ventilator operating parameters and one or more pacing parameters, monitor respiratory cycle signals, determine inspiratory and expiratory phases of the respiratory cycle, generate stimulation signals in response to the one or more pacing parameters, and deliver the generated stimulation signals to at least one transvascular electrode at preselected times in the respiratory cycle, and adjust the patient's diaphragmatic output from one respiratory cycle to the next.

[0034] According to a twenty-eighth embodiment, the controller is further programmed to adjust the patient's diaphragmatic output to meet the patient's prescribed level of assistance. According to a twenty-ninth embodiment, the controller is further programmed to maintain synchronization of the delivery of the stimulation signal with the ventilator breathing cycle.

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

[0036] According to a thirty-first embodiment, the controller is programmed to monitor the diaphragm output by sensing diaphragm output data by one of one or more sensors and processing the sensed diaphragm data to determine the diaphragm output, the diaphragm output including parameters derived from flow, tidal volume and / or pressure, and / or a combination of flow, tidal volume and / or pressure.

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

[0038] According to a thirty-third embodiment, the controller is further programmed to account for when the diaphragm output of the last administered stimulation signal is outside a preselected target range.

[0039] According to a thirty-fourth embodiment, if the controller determines that the cause is due to a change in the patient's respiratory mechanics, the controller is further programmed to evaluate the condition of the patient's diaphragm and respiratory system during administration of the treatment plan.

[0040] According to a thirty-fifth embodiment, the controller is further programmed to reprogram the stimulation signal based on the assessed diaphragm condition. According to a thirty-sixth embodiment, the controller is further programmed to assess the diaphragm by monitoring data representative of flow and pressure of the ventilator breathing cycle to determine a timing of end-expiratory delay, progressively stimulating the diaphragm with 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. 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.

[0041] According to a thirty-seventh embodiment, the controller is further programmed to determine readiness for weaning from the ventilator based on assessment of the diaphragm. According to a thirty-eighth embodiment, the stimulation signal includes a doublet or 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 of preventing respiratory disuse atrophy in a patient who is mechanically ventilated and receiving respiratory assistance and sedation with a ventilator breathing cycle is provided, the method comprising the steps of placing a first electrode in the patient's vasculature proximate to the left phrenic nerve, placing a second electrode in the patient's vasculature proximate to the right phrenic nerve, and delivering preprogrammed stimulation signals to the first and second electrodes to stimulate the diaphragm in synchrony with the ventilator breathing cycle within a few hours that the patient is on the ventilator.

[0043] According to a thirty-ninth 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 regimen for preventing or hastening the reversal of diaphragm disuse atrophy in a patient receiving respiratory assistance from a ventilator, the ventilator providing breathing cycles to the patient, the patient having a prescribed level of assistance, the method including storing measurements representative of a preselected range of diaphragm output that is at least a portion of the prescribed level of assistance, monitoring the ventilator breathing cycles, administering a stimulation signal to the patient in phase with the ventilator breathing cycles to recruit the patient's diaphragm to produce a level of diaphragm output, and adjusting the patient's diaphragm output from diaphragm recruitment for each stimulated breathing cycle to fall within the preselected range of diaphragm output.

[0044] According to a fortieth embodiment, adjusting the patient's diaphragm output for each respiratory cycle includes monitoring the diaphragm output in response to a last administered stimulation signal and comparing the diaphragm output of the last administered stimulation signal with a preselected range of diaphragm output.

[0045] According to a forty-first embodiment, monitoring diaphragmatic output in response to a last administered stimulation signal includes sensing diaphragmatic output data by one or more sensors and processing the sensed diaphragmatic output data to determine diaphragmatic output. In some embodiments, diaphragmatic output includes one or more of airflow, tidal volume, pressure, and / or parameters derived from a combination of flow, tidal volume, and / or pressure.

[0046] According to a forty-second embodiment, adjusting the patient's diaphragm output for each respiratory cycle further includes comparing the determined diaphragm output with a preselected range of diaphragm output and modifying the stimulation signal to be administered with the next ventilator breath if the diaphragm output from the last administered stimulation signal falls outside the preselected range of diaphragm output.

[0047] According to a forty-third embodiment, modifying the stimulation signal includes increasing the strength of the stimulation signal. According to a 44th embodiment, increasing the strength of the stimulation signal includes one or more of increasing the frequency of the stimulation signal pulses, increasing the amplitude of the stimulation signal pulses, and / or increasing the duration of the stimulation signal pulses.

[0048] According to a forty-fifth embodiment, the diaphragmatic output includes tidal volume, pressure, or a combination thereof. According to yet another aspect of the present disclosure, there is provided a method of preventing disuse atrophy of the diaphragm in a critically ill patient, the method comprising the steps of: placing the patient on a ventilator, monitoring the respiratory cycles of the ventilator, administering a preprogrammed stimulation signal to the patient during one of a 12 hour or 6 hour period that the patient is on the ventilator to recruit the patient's diaphragm to output a level of diaphragmatic output, and adjusting, for each respiratory cycle, the level of the patient's diaphragmatic output to meet or exceed a preselected threshold based on administration of the stimulation signal.

[0049] According to yet another aspect of the present disclosure, there is provided a method of developing a treatment plan for a patient, the treatment plan seeking to prevent disuse atrophy or restore the patient's diaphragm, the method including the steps of evaluating the diaphragm for maximum diaphragmatic output and fatigue characteristics, and determining one or more stimulation signals that result in diaphragmatic output at a preselected percentage of the maximum diaphragmatic output.

[0050] According to a forty-sixth embodiment, the method further includes creating a stimulation regimen including a series of individual stimulation signals, which may vary in rate, duration, pulse width, frequency, and amplitude.

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

[0052] According to yet another aspect of the present disclosure, a transvascular diaphragmatic pacing system is provided for developing a treatment plan for a patient. The treatment plan, in some embodiments, prevents diaphragm disuse atrophy or restores the patient's diaphragm. The system includes at least one intravascular electrode configured to deliver a delivered 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 sense a respiratory cycle signal from an associated ventilator and a diaphragm response due to recruitment of the phrenic nerve, a pulse generator coupled in electrical communication with the at least one intravascular electrode, and at least one input device configured to input data representative of one or more aspects of the treatment plan. The system further includes a controller coupled in electrical communication with the one or more sensors, the at least one input device, and the pulse generator. The controller, in some embodiments, is programmed to evaluate the diaphragm for maximum diaphragmatic output and fatigue characteristics and determine one or more stimulation signals that will bring the diaphragmatic output to a preselected percentage of the maximum diaphragmatic output.

[0053] According to yet another aspect, a transvascular diaphragm pacing system for assessing the diaphragm is provided. The system includes at least one intravascular electrode configured to deliver a delivered 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 sense a respiratory cycle signal from the ventilator and a diaphragmatic response due to recruitment of the phrenic nerve, a pulse generator coupled in electrical communication with the at least one intravascular electrode, and at least one input device configured to input data representative of one or more aspects of a treatment plan. The system further includes a controller coupled in electrical communication with 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 representative of flow and pressure of the ventilator respiratory cycle; stimulate the diaphragm with a stimulation signal based on the monitored data of the ventilator respiratory cycle; and determine one or more functional characteristics of the diaphragm from a response evoked by stimulating the diaphragm with 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.

[0054] This Summary is provided to introduce in a simplified form a selection of concepts that are further described below in the Detailed Description. 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 determining the scope of the claimed subject matter.

[0055] The foregoing aspects and many of the attendant advantages of the claimed subject matter will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 is a schematic diagram of an example of a transvascular diaphragmatic pacing system formed in accordance with an embodiment of the present disclosure. [Diagram 2] 1 is a schematic diagram of the location of a patient's left and right phrenic nerves relative to the patient's heart and diaphragm. [Figure 3A] FIG. 1 is an example of a pair of catheter-mounted phrenic nerve stimulating electrodes positioned within a patient's left subclavian vein. [Figure 3B] FIG. 1 is a diagram of an example pair of catheter-mounted phrenic nerve stimulating electrodes positioned within a patient's superior vena cava. [Figure 4] FIG. 2 is a block diagram of components of one embodiment of the system of FIG. 1. [Diagram 5] Diagram showing the shift in force generated when stimulating with a train starting with a doublet / triplet. [Figure 6] FIG. 13 shows an example of the programmable parameters of each stimulation pulse when illustrating net charge, as well as the ratiometric relationship between charge injection and charge balancing pulses. [Figure 7] FIG. 1 shows an example of a three stimulation train in which the pulse width and frequency are modulated in each train such that they increase from the beginning to the end of the stimulation train to induce a gradual contraction of the diaphragm. [Figure 8] FIG. 1 shows an example of a three stimulation train in which the pulse width and frequency are modulated in each train such that they first increase and then decrease from the beginning to the end of the stimulation train to induce a graded contraction of the diaphragm. [Figure 9] FIG. 13 shows an example of a representative slope envelope, where the slope angle represents the modulation of pulse width and / or pulse frequency within a train. [Figure 10] FIG. 13 shows examples of representative pulse width slope envelopes and stimulation frequency envelopes that can be combined together to form a single pacing slope. [Figure 11] FIG. 13 illustrates an example of timing of start and end points of stimulation trains generated and delivered to the phrenic nerve in relation to ventilator breathing. [Figure 12] FIG. 13 illustrates another example of the timing of the start and end of a stimulation train generated and delivered to the phrenic nerve. [Figure 13] FIG. 13 illustrates yet another example of timing and amplitude modulation of stimulation trains generated and delivered to the phrenic nerve. [Figure 14] FIG. 1 illustrates an example of a method configured to perform one or more functions of system 20, including, but not limited to, a ventilator-initiated pacing mode. [Figure 15] 15 illustrates one feedback scheme that can be implemented by the method of FIG. 14 and the system of FIG. 1. [Figure 16] FIG. 1 shows an example of changes in respiratory mechanics during synchronized pacing with a volume-controlled mechanical ventilator. [Figure 17A] FIG. 13 shows an example of maintaining diaphragmatic output at a prescribed level despite time-dependent fatigue and dropout of stimulated type IIb fibers. [Figure 17B] FIG. 13 shows an example of maintaining diaphragmatic output at a prescribed level despite time-dependent fatigue and dropout of stimulated type IIb fibers. [Figure 17C] Diagram showing how to use duos to increase the force of fatigued muscles. [Figure 18] FIG. 1 shows an example of progressive recruitment of nerve axons across a cross section of the phrenic nerve and its associated motor units with increasing pacing intensity. [Figure 19] Scale the contribution of the system of FIG. 1 to a prescribed assist level, for example using a binary algorithm, and display the resulting graph to determine one or more initial pacing parameters. [Figure 20A] Schematic of an example of scaling the contributions of the system in Figure 1 to the diaphragm response. [Figure 20B] FIG. 2 is a schematic diagram of another example of scaling the contributions of the system in FIG. 1 to the diaphragm response. [Figure 21] FIG. 1 is a graphical representation of an example where the work of breathing (WOB) is calculated, which is then used to adjust the diaphragm contribution. [Figure 22] An example of a routine diaphragm assessment without disconnecting the patient from the ventilator. [Figure 23]FIG. 13 shows an example of timing of administered stimuli relative to phases of the respiratory cycle. [Figure 24] FIG. 13 shows an example of timing of administered stimuli relative to phases of the respiratory cycle. [Diagram 25] Graphical representation of airway pressure data obtained from a volume-controlled ventilator with and without stimulation. [Figure 26] Graphical representation of an example where the pressure-time product is calculated and that calculation is then used to modulate the diaphragmatic contribution. [Figure 27] FIG. 2 is a diagram of an example evaluation routine executed by the system of FIG. 1. [Figure 28] Graphical representation of the end-expiratory pause, sometimes called the quiet period. [Figure 29] FIG. 13 is an example of a routine for determining the duration of the end-tidal pause. [Diagram 30] 2 is a schematic diagram illustrating an example of a pacer-initiated ventilation mode that may be implemented by one or more embodiments of the system shown in FIG. 1. [Diagram 31] Diagram showing the relationship between the pacing system and the ventilator in Pacer-Initiated Ventilation mode. [Diagram 32] Schematic diagram showing an example of a pacing system operating in autonomous mode. [Figure 33A] 2 is a graph illustrating the benefit of one example of the system of FIG. 1 in preventing diaphragm disuse atrophy or restoring the diaphragm for successful weaning from respiratory assistance. [Figure 33B] 2 is a graph illustrating the benefit of one example of the system of FIG. 1 in preventing diaphragm disuse atrophy or restoring the diaphragm for successful weaning from respiratory assistance. [Figure 33C] 2 is a graph illustrating the benefit of one example of the system of FIG. 1 in preventing diaphragm disuse atrophy or restoring the diaphragm for successful weaning from respiratory assistance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] The detailed description set forth below in conjunction with the accompanying drawings, in which like numerals refer to like elements, illustrates one of various embodiments of the disclosed subject matter and is not intended to represent embodiments only. 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 intended to be exhaustive or to limit the claimed subject matter to the precise form disclosed.

[0058] The following discussion presents examples of transvascular diaphragmatic pacing systems (TDPS) and methods of administering respiratory therapy to patients. Some examples of TDPS involve rapid insertion and placement of intravascular pacing electrodes in critically ill patients who require intubation and invasive PPMV to support the physiological requirements of the human ventilatory system. Examples described herein take best advantage of the contractile properties of the diaphragm muscle to prevent muscle disuse atrophy and muscle wasting. This can be done by coupling the phrenic nerve with patterned functional electrical stimulation applied to intravascular electrodes that are temporarily and reversibly inserted into the patient's central veins, such as the left subclavian vein and superior vena cava. In some examples, the TDPS is designed to seamlessly interface with any commercially available positive pressure ventilation support / assistance device, such as those typically used in hospital intensive care units (ICUs) to treat critically ill patients with respiratory failure, pain, trauma, sepsis, or neurological diseases or deficits.

[0059] Rapid insertion and deployment of the disclosed system can be accomplished by using a minimally invasive central line catheter-based electrode, such as that described in U.S. Patent Application Serial No. 12 / 524,571, filed July 25, 2009. The electrode can be quickly attached to the patient under local anesthesia and rapidly activated, allowing pacing therapy to begin within an hour or a few hours of admission / intubation. If the patient's clinical condition suggests, electrical stimulation pacing can continue in sync with ventilator breathing, provided by virtually any brand or model of commercially available positive pressure ventilator operating in a typical mode, such as control mode, support mode, or assist mode. After therapy is completed, the pacing catheter electrode can be easily removed. In some embodiments, the system pacing tracks the operation of the ventilator, and in other embodiments, the ventilator initiates and / or assists the respiratory cycle based on the physiological response generated by the pacing system.

[0060] Rapid deployment (i.e., within hours of admission / intubation) is advantageous in preventing the pathological effects of muscle disuse atrophy, which is known to occur very quickly in mechanically ventilated and sedated patients, and in maintaining the strength and endurance of the diaphragm muscle during periods of critical illness when the patient is unable to breathe independently. Figures 33A-C show an example of using TDPS to prevent diaphragm disuse atrophy or to restore the diaphragm to successful weaning from respiratory support. As a result, early and successful weaning from the ventilator may be achieved. Another advantage arising from the rapid deployment functionality of the system described herein and the rapid initiation of diaphragm pacing therapy is that this intervention helps prevent / reduce the adverse effects of high airway / positive lung pressures (such as ventilator-induced lung injury (VILI)) commonly encountered by mechanically ventilated patients, which often contribute to the inability to wean and long-term dependence on mechanical ventilation. Patients who remain mechanically ventilated are at high risk for ventilator-associated pneumonia (VAP) and for acquiring hospital-acquired (hospital-born) infections. It is therefore important to ensure that mechanically ventilated patients are weaned from ventilation as quickly as medically possible. The example pacing systems and methods described herein address this need and others.

[0061] As described in more detail below, the disclosed system is designed to stimulate the right phrenic nerve (recruiting the right hemidiaphragm), the left phrenic nerve (recruiting the left hemidiaphragm), or both phrenic nerves to recruit the entire diaphragm muscle. Additionally, each phrenic nerve may be recruited using a single stimulation channel per nerve, or two or more stimulation channels. An example illustrating one embodiment using two stimulation channels per phrenic nerve is provided in FIG. 3. In some examples using two stimulation channels per nerve, stimulation pulses that are 180 degrees out of phase 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. However, it will be apparent to one of ordinary skill in the art that many embodiments of the present disclosure can be practiced without some or all of these specific details. In some instances, well-known method steps have not been described in detail in order not to unnecessarily obscure various aspects of the present disclosure. Furthermore, it should be understood that any combination of the features described herein may be used in embodiments of the present disclosure.

[0063] Referring now to FIG. 1, there is shown an example of a transvascular diaphragmatic pacing system, generally designated 20, formed in accordance with aspects of the present disclosure. As best shown in FIGS. 1 and 4, the system 20 includes a stimulator 24 coupled in electrical connection (e.g., wired or wireless) with one or more transvascular electrodes 28 adapted for internal placement near the left and / or right phrenic nerve. In use, the stimulator 24 is configured to transmit a stimulation signal in the form of a stimulation pulse to one or more of the electrodes 28. The electrodes 28 then emit a stimulation signal near the left and / or right phrenic nerve. Stimulation of the left and / or right phrenic nerve is then aimed at causing recruitment of the patient's diaphragm.

[0064] As described in more detail below, parameters of the stimulation pulses (amplitude, duration, frequency, etc.) affect the amount of diaphragmatic recruitment and the resulting output (tidal volume, pressure, etc.). In that regard, and as described in more detail below, sensors 48 configured to sense various physiological parameters of the patient can provide feedback to the stimulator 24, in part indicative of diaphragmatic output, for control of the therapy being administered.

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

[0066] The patient's respiratory needs may be referred to as the patient's prescribed level of support. This prescribed level of support is generally quantified as the amount of tidal volume or pressure (or a combination of the two) delivered to the patient during one respiratory cycle that satisfies the patient's minimal physiological function. Generally, the prescribed level of support is approximately 7-10 mL per kg of patient weight in terms of tidal volume. In some embodiments, the prescribed level of support is met solely by artificial means (e.g., by system 20, by ventilator 32, or by a combination of the two). This may be done with a heavily sedated and / or unconscious patient. In another embodiment, the prescribed level of support may include some respiratory 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 the system 20 to meet a prescribed level of support (i.e., tidal volume, pressure, or both levels) through diaphragmatic recruitment. In another embodiment, the clinician can program the system 20 to contribute a percentage value of the prescribed level of support (volume, pressure, or both levels), referred to herein as the diaphragmatic contribution or diaphragmatic contribution level, through electrical recruitment of one or more phrenic nerves. This percentage can vary and is patient-dependent based on various factors such as the physical condition of the patient, the illness afflicting the patient, the time elapsed before any stimulation therapy, etc. In this embodiment, the remaining percentage of the prescribed level of support can then be met by the ventilator 32, which can be appropriately programmed at the beginning or during the application of the treatment plan by the clinician.

[0068] In some embodiments, as described in more detail below, system 20 performs one or more assessments of the patient to determine, for example, 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, submaximal pulse width, and supramaximal pulse width. Threshold pulse width refers to the minimum pulse width above which there is a diaphragmatic response. Threshold frequency refers to the lowest frequency above which partial or fully fused tetanus occurs to generate effective diaphragmatic force and / or action.

[0069] 2, the placement of electrodes 28 will be described with respect to the heart H and diaphragm D of patient P. As shown in FIG. 2, the left and right phrenic nerves course along the lateral and medial sides of the heart to the diaphragm D. The left subclavian vein traverses adjacent to the left phrenic nerve and carries blood from the upper extremities to the heart H. The superior vena cava traverses adjacent to 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 stimulus in the form of voltage (V), current (mA) or charge (nanocoulombs), the phrenic nerve is activated and the diaphragm D will contract.

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

[0071] The components of the system will now be described in detail with reference to Figure 4. As shown in Figure 4, the system 20 includes a first electrode 28A having anodal and cathodal electrode contacts 30A, 32A disposed within the left subclavian vein and positioned adjacent to the left phrenic nerve. In the illustrated embodiment, a second electrode 28B having anodal and cathodal electrode contacts 30B, 32B may also be disposed within the left subclavian vein and positioned adjacent to the left phrenic nerve.

[0072] The system 20 further includes a third electrode 28C having anodal and cathodal electrode contacts 30C, 32C disposed within the superior vena cava and positioned adjacent the right phrenic nerve. In the illustrated embodiment, a fourth electrode 28D having anodal and cathodal electrode contacts 30D, 32D may also be disposed within the superior vena cava and positioned adjacent 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 more information regarding placement of multiple electrodes within a blood vessel, as well as the configuration of one type of electrode structure that can be implemented with the embodiments of the present disclosure, see U.S. Patent Application No. 12 / 524,571, filed July 25, 2009, the disclosure of which is expressly incorporated herein by reference in its entirety. In addition, although electrodes having anodic and cathodic electrode contacts are utilized to emit stimulation pulses into the phrenic nerve, other configurations are possible. For example, several cathodic electrode contacts can be used in combination with a single anodic electrode contact, and vice versa.

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

[0075] The term "volume" as used herein includes, but is not limited to, "inspired tidal volume," "expired tidal volume," or "minute volume." The term "pressure" as used herein 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 intrathoracic pressure. Any pressure may be a peak pressure, a mean pressure, or a baseline pressure. The term "flow" as used herein includes, but is not limited to, inspiratory flow or expiratory flow.

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

[0077] In some embodiments, the system 20 further or alternatively includes a respiratory sensor 50 for sensing parameters of the ventilator 32. In that regard, the respiratory sensor 50 may be configured to interface with any standard breathing circuit used in critical care ventilators, such that the pacing system is independent of the brand of ventilator used. Depending on its location in the breathing circuit, the respiratory sensor 50 may monitor and / or measure several respiratory parameters and communicate such parameters to the stimulator 24. As described in more detail below, the respiratory sensor 50 may be part of, or used alone as, a feedback control system for regulating the stimulation provided to the patient. Sensed respiratory parameters may include, but are not limited to, airflow (inhaled and / or exhaled), volume, pressure (airway, esophageal, stomach, and / or any combination / derivative of the former). In some embodiments, other sensors may aid in obtaining one or more respiratory parameters.

[0078] In some embodiments, the exemplary parameters are measured both to and from the ventilator 32. In the illustrated embodiment, the breath sensor 50 is external to the ventilator 32, so the system is ventilator model independent. However, the system 20 can also be integrated to use internal sensors of the ventilator that can provide information to the system 20 for proper operation, or to use signals provided externally by the ventilator, such that an external breath sensor can be omitted.

[0079] The stimulator 24 functions, in part, as a signal generator to provide diaphragmatic therapy in response to information received from one or more of the sensors 48 and 50 and / or information programmed into the system 20 by the clinician. In that regard, the stimulator 24 delivers pulses to the intravascular electrodes 28 according to one or more protocols described herein. As described in more detail below, the pulses are generated in some embodiments by the stimulator 24 having characteristics to deliver an appropriate charge to the phrenic nerve to achieve diaphragmatic recruitment sufficient to meet the selected diaphragmatic contribution (e.g., volume, pressure, both, or parameters derived from volume and pressure) of the prescribed assistance level discussed above.

[0080] To this end, the stimulator 24 is configured to deliver fully programmable stimulation, including, but not limited to: any number of pulses, any combination of prescribed pulses, any sequence of delivery of prescribed pulses, multiple instances of any prescribed pulse, any frequency of stimulation, and / or any delay between pulses (inter-pulse delay). Each pulse may be separately programmable (e.g., frequency, amplitude, duration, etc.). Stimulation pulses and / or trains may or may not produce repeatable patterns.

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

[0082] Since the diaphragm is a skeletal muscle, pacing can be achieved by delivering one or more stimulation signals to produce mechanically effective contractions of the diaphragm. In this regard, the stimulation signal can include multiple pulses grouped as a stimulation train. A stimulation train is defined herein as a collection of stimulation pulses. This definition does not imply a particular composition, order of delivery, and / or shape contour or envelope. Figures 7 and 8 show examples of stimulation trains generated by the stimulator 24 and delivered to the electrode 28 to stimulate the phrenic nerve. Stimulation trains can start with a duo (pair of pulses) or a triplet, which can be physiologically relevant. That is, as shown in Figure 5, two or three pulses in rapid succession at the beginning of the escape have been found to raise the overall force profile by shifting the baseline up at the initial onset of the escape. Similarly, a duo or triplet delivered partway through the train can produce a sustained increase in force. An upward shift in initial force production means that the same amount of force can be generated from the diaphragm over a comparable period of time using fewer stimulation pulses. This can be highly advantageous, since overactivating the diaphragm with an excessive number of stimulation pulses can induce fatigue and can also cause conversion of fast-twitch fibers (powerful but prone to fatigue) to slow-twitch fibers (fatigue-resistant but unable to generate significant force).

[0083] Stimuli or pulse trains are typically characterized by their rate, duration, pulse width, frequency, and signal amplitude. The rate of a stimulation train refers to the number of stimulation trains delivered per minute, which can be correlated to the patient's breathing rate or mechanical ventilator rate. The duration of a stimulation train refers to the length of time the stimulation train is delivered. Pulse width refers to the duration of each individual pulse that makes up the stimulation train. Similarly, frequency refers to the number of individual pulses delivered per second. Finally, amplitude refers to the voltage of each delivered pulse. The parameters of amplitude, frequency, and pulse width determine the strength of the induced diaphragmatic pacing.

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

[0085] Varying the pulse width and frequency modulation allows for the design of various gradient train envelopes. With reference to FIG. 9, it is possible to generate gradient envelopes of pulse width only, frequency only, or both pulse width and frequency during a single pacing gradient. The envelopes of pulse width and stimulation frequency can be modulated together, i.e., combined, during pacing to generate a desired gradient train, as shown in the example of FIG. 10. For example, combination AF provides gradual recruitment of phrenic motor neurons at a constant frequency (no rate coding), while combination BA progressively recruits and de-recruits motor neurons with gradually increasing rate coding, although any combination is possible. It is also possible to change the rate (slope) of recruitment and de-recruitment of motor neurons independent of rate coding by adjusting the relative percentage of duration of pulse width increase and decrease within a single pacing gradient. Furthermore, pulse width modulation and frequency modulation can be mathematically defined as piecewise functions of time, thereby allowing any desired gradient envelope to be generated while remaining within the scope of the present disclosure.

[0086] While numerous sets of gradient trains can be generated, there are several embodiments in which gradient trains aim to achieve one or more of the following: 1) mimic the physiological contraction of the diaphragm by separately controlling recruitment and rate coding using pulse width modulation and frequency modulation, respectively; 2) delay the onset of motor neuron fatigue; 3) preserve the natural fiber composition of a healthy diaphragm; 4) condition the diaphragm to a specific fiber type, for example type 1 (slow twitch fibers, fatigue resistant).

[0087] A treatment plan can be constructed by the clinician with or without the aid of the system 20 using various programmable stimulation or ramp sequences. The treatment plan constructed by the clinician is patient dependent to achieve various goals. The treatment plan can include one or more of the following: timing of pacing delivery relative to ventilator breathing (e.g., every breath, every other breath, every fifth breath, etc.), intermittent stimulation segments (e.g., 15 minutes of stimulation delivery every hour), etc. As an example, for a patient who requires PPMV and sedation, the treatment plan takes into account both primary objectives: minimizing VIDD and minimizing the risk of VILI. As another example, in a treatment plan for a patient who can be awake for part of the day, can breathe independently for several hours, and will soon be weaned, it may be desirable not to pace while the patient is spontaneously breathing, but conversely, during the night when the patient is again sedated and placed back on PPMV, it may be desirable to pace at a low assist level to reduce the peak pressure required for breathing and thus the risk of VILI.

[0088] In some embodiments, the treatment plan includes a feature to skip stimuli, sometimes called skip breaths, which allows ventilator breaths to be delivered without stimulation from the 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 greater magnitude stimulation train) than normal breaths. This results in a more forceful diaphragm contraction, physiologically. Both characteristics are separately programmable and can be repeatable. For sigh breaths alone, the amplitude ratio increase is programmable based on the amplitude of a typical paced breath. These characteristics can be implemented separately or in combination.

[0089] 13A-C show examples of skipped breaths, sigh breaths, and a combination of skipped and sigh breaths, respectively. FIG. 13A shows an example of skipped breaths, 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, breathing mechanics such as tidal volume, lung compliance, airway resistance, or lung area recruitment may change. FIG. 13B shows an example of sigh breaths generated by the system 20 while operating in synchrony with the ventilator 32. In this example, a sigh breath is delivered every third breath. Depending on whether it is flow or pressure controlled, the sigh breaths can change breathing mechanics. This characteristic mimics the characteristic of spontaneous breathing, i.e., variable tidal volume. FIG. 13C shows an example of both skipped and sigh breaths delivered periodically by the system 20.

[0090] The stimulator 24 in some embodiments is configured to generate constant amplitude current pulses with pulse durations ranging from 50 to 300 microseconds controllable in 10 microsecond increments. The amplitude and duration of each pulse in the train is separately programmable. The amplitude of the pulses can be selected between 0.1 and 10 mA in 0.1 mA increments. 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) x Pulse Duration (in microseconds). In this regard, the stimulator 24 can generate pulses ranging from 5 nC to 3000 nC, with the charge per pulse being specifiable in 1 nC increments.

[0091] FIG. 4 shows a schematic diagram of one embodiment of the stimulator 24. As shown in FIG. 4, the stimulator 24 includes a controller 60, which receives sensed signals from one or more sensors 48 and / or respiration sensor 50. The stimulator 24 may also include a timer 64 coupled to the controller 60, and a power supply 68. The controller 60 is coupled to a pulse generation circuit 70, which delivers stimulation signals to one or more of the electrodes 28 via the leads 40. In one embodiment, the above-mentioned components are coupled via a bus 72. In some embodiments, the power supply 68 of the stimulator 24 includes one or more batteries. In another embodiment, the power supply 68 includes a power conditioning section, which receives power from a standard "mains power source" and converts it to power appropriate for the circuitry of the stimulator 24.

[0092] Those skilled in the art will appreciate that the controller 60 serves as the computational center of the stimulator 24 for executing logic or by assisting in the execution of routines, instructions, etc. that provide functionality to the stimulator 24. In that regard, the logic, routines, instructions, etc. described herein may be implemented in hardware, software, or a combination of hardware and software.

[0093] In some embodiments, the controller 60 includes one or more processors and memory. The logic, routines, instructions, etc. may include, for example, a set of control algorithms, including resident program instructions and calibrations, stored in the memory and executed to obtain the desired function of the system 20. These algorithms may be executed during preset loop cycles, such that each algorithm is executed at least once per loop cycle. The algorithms stored in the non-volatile storage medium may be executed by the processor to: 1) monitor inputs from the sensors 48, 50 and other data transmitting devices, or poll these devices for data to be used by the processor, 2) cause the pulse generator to generate and deliver one or more pulses to the electrodes 28, and 3) regulate the patient's diaphragm output, among other functions. The loop cycles are executed at regular intervals during ongoing operation of the system 20, for example, every 3.125 ms, 6.25 ms, 12.5 ms, 25 ms, and 100 ms. Alternatively, the algorithms may 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 in the art as computers, but refers broadly to microcontrollers, microcomputers, microprocessors, programmable logic controllers, application specific integrated circuits, other programmable circuits such as programmable gate arrays, and combinations of the above, among others. In some embodiments, controller 60 may include additional components, including, but not limited to, high speed clocks, analog-to-digital (A / D) and digital-to-analog (D / A) circuitry, input / output circuits and devices (I / O), and appropriate signal processing and buffering circuitry.

[0095] It should be appreciated that signals received from the sensors 48, 50 may be processed by an optional signal processor 80 before reaching the controller 60. For example, the signal processor 80 may include dedicated circuitry, a processor such as a digital signal processor (DSP), etc., for receiving, processing and filtering electrical signals sensed by sensors associated with the patient and / or the ventilator 32. The signal processor 80 may include amplifiers and circuitry for processing, filtering and / or amplifying the electrical signals provided thereto. In some embodiments, the signal processor 80 performs separate tasks such as determining one or more physiological conditions. One physiological condition that may be determined by the signal processor 80 is the patient's minute respiratory volume or ventilation. Minute ventilation is a breathing-related parameter that is a measure of the amount of air inspired and expired during a particular period of time. Minute ventilation is the product of breathing rate and tidal volume. The signal processor 80 may also be used to receive and process signals representative of other respiratory activities such as intrathoracic pressure, chest wall movement, etc. Of course, determining one or more physiological conditions, processing signals, implementing logic or processes, etc. may be performed solely by the controller 60 .

[0096] 4, the stimulator 24 includes one or more input devices 86. The input devices 86 may include switches, knobs, etc. carried by the stimulator housing, and / or computer-style devices such as a keyboard, touchpad, etc. The input devices 86 may input data, such as pacing parameters, ventilator parameters, etc., into the stimulator 24. An output device 92, such as a monitor, may also be provided.

[0097] In accordance with aspects of the present disclosure, one or more embodiments of system 20 may be operated in various pacing modes. The pacing modes may alternatively be used by clinicians depending on the clinical condition and needs of each patient, and on the operating characteristics of ventilators, such as ventilator 32, that may be available in a particular ICU. The pacing modes may include, but are not limited to, ventilator-initiated pacing modes, pacer-initiated breathing modes, and autonomous pacing modes. Those skilled in the art will appreciate that these modes may be engaged in many ways to create various combinations of system functionality, but for the sake of brevity, not all possible combinations are enumerated herein. Each of these modes will now be described in some detail.

[0098] The first mode of the system 20 described herein is a ventilator-initiated pacing mode. As described in more detail below, this mode causes the stimulator 24 to operate in synchrony with the operation of the ventilator 32. This mode can function with any mechanical ventilator as a control mode in which flow or pressure is controlled by the ventilator and delivered at a predefined frequency (breathing rate). Delivery of the stimulation ramp train generated by the stimulator 24, such as any of those shown in Figures 9 and 10, can be synchronized with the ventilator 32 in a number of ways, some of which are shown in Figures 11 and 12. For example, stimulation can begin any time before, during or after the initiation of the inspiratory phase of the ventilator 32, and / or can end any time before, during or after the termination of the inspiratory phase of the ventilator 32.

[0099] Referring now to FIG. 14, an example routine 100 configured to perform one or more functions of the system 20, including a ventilator-initiated pacing mode, is shown. As will be appreciated by those skilled in the art, the logic or routines described herein may represent one or more of any number of processing strategies, such as event-driven, interrupt-driven, multitasking, multithreading, etc. Thus, the various activities or functions illustrated may be performed in the order shown, in parallel, or omitted. Similarly, the order of processing is not necessary to achieve the functionality and advantages, but is provided for ease of illustration and description. Although not explicitly illustrated, one or more of the illustrated activities or functions may be performed repeatedly depending on the particular strategy used. Some of the functions performed by the routines may be combined or further divided into additional steps or activities.

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

[0101] In some embodiments, the clinician can input the prescribed level of patient assistance depending on the clinical condition. In some embodiments, the prescribed level of assistance is programmed as a tidal volume. Alternatively, the prescribed level of assistance can also be programmed as: (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 monitored variables, such as the pressure-time index (PTI), or (5) the reduction in airway pressure obtained by adding pacing to PPMV compared to PPMV alone. The prescribed level of assistance can be set with respect to one of the above parameters or as a combination of one or more of these parameters while remaining within the scope of the claimed subject matter.

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

[0103] The clinician may also input the amount of therapy to be provided per 24-hour period. For example, the clinician may wish to provide therapy for only 8 hours out of a 24-hour period. The therapy may be provided continuously for 8 hours or may be divided into time division blocks (e.g., 2 hours, 1 hour, 30 minutes, 15 minutes, etc.), which may be fixed or variable. If variable, the time division blocks may form a repeatable pattern, as desired. The therapy may also vary the diaphragm contribution throughout the period of stimulation administration. In some embodiments, the clinician may program sigh or skip breaths, as described above with reference to FIGS. 13A-C. The clinician may also input one or more respiratory parameters, such as ventilator operating mode, respiratory cycle timing (i.e., breaths per minute), etc. It is understood that other data may be input by the clinician during the initialization phase that provides functionality to the system 20.

[0104] Returning to FIG. 14, the routine 100 proceeds to block 104 where the respiratory cycle of the patient and / or ventilator is monitored. In one embodiment, the routine 100 executes a breath detection algorithm that uses data from the breath sensor 50 to detect various phases of ventilator breathing or spontaneous breathing, such as an inspiration phase, an inspiration pause, an expiration phase, and an expiration pause. Additionally, the breath detection algorithm may also quantify various breath attributes, such as the duration of any of the above-mentioned breath phases. The breath detection algorithm may use any of the monitored signals, such as flow, volume, or pressure, to evaluate a series of conditional equations to identify and / or calculate attributes of the respiratory cycle. Methods for identifying and / or calculating attributes of the respiratory cycle may include, but are not limited to, slope threshold detection, amplitude threshold detection, or combinations thereof. Additionally, the breath detection algorithm may store and / or process any set of waveform data for the current breath or previous breaths. The breath detection algorithm may also facilitate operating the system in an event-predictive or event-triggered manner. If a spontaneous breath is detected, the system can stop ongoing stimulation or continue stimulation and allow the spontaneous breath to increase or skip the next breath.

[0105] Next, in block 106, synchrony is maintained between the ventilator 32 and the administration of the pacing therapy. This ensures that diaphragmatic pacing by the stimulation signals emitted from the electrodes is synchronized with each breath delivered by the ventilator 32. If a lack of coupling is suspected, pacing can be skipped and resumed immediately after the ventilation pattern has re-stabilized. In another embodiment, pacing can be continued while synchrony is being re-established. In some embodiments, synchrony can be determined by comparing attributes of at least one previous breathing cycle (e.g., 12 breaths per minute, etc.) with attributes of a current breathing cycle of the ventilator 32 as determined by processing signals from the breathing sensor 50 and / or from one or more of the sensors 48.

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

[0107] If the calculated diaphragm contribution resulting from the last applied stimulation signal differs from the target diaphragm contribution value by more than a preselected amount, the stimulation parameters can be modified (e.g., amplitude and / or duration are increased) to maintain the diaphragm output within a desired range. Such a difference between the calculated diaphragm contribution corresponding to the last applied stimulation signal and the programmed diaphragm contribution value can be seen as a change in pressure (in volume-controlled modes / ventilators) or as a change in tidal volume (in pressure-controlled modes / ventilators), or as a change in any signal sensed by one or more of sensors 48 or sensor 50. The modified stimulation parameters are then 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 evaluation is performed to determine 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 stimulation electrodes being displaced far from the optimal position. In another embodiment, the difference or variability in tidal volume or pressure between breaths may be due to changing patient respiratory mechanics or time-dependent fatigue of higher force producing and fast tiring (type IIb) fibers.

[0109] Changes in breathing mechanics may include changes in airway resistance and / or changes in lung / chest wall compliance. For example, in the embodiment shown in FIG. 16, the tidal volume is controlled during every breath, which corresponds to the ventilator operating in a volume-controlled mode. If any change in resistance or compliance load occurs, this change is reflected as a change in airway pressure, which is graphed below the tidal volume. In the example of FIG. 16, the first two breaths show baseline levels 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 an increase in peak airway pressure and a change in the slope of the airway pressure waveform.

[0110] By the fourth breath shown in Figure 16, system 20 can examine the decrease in measured compliance and attribute it to, for example, a reduced force contribution of fast fatigable type IIb fibers. By the fifth breath, system 20 has adjusted its pacing parameters to restore the desired level of diaphragm contribution (negative pressure) to the entire ventilatory support system, thereby returning airway pressure to the prescribed support level.

[0111] It will be appreciated that similar principles may be applied to pressure-controlled ventilators, where changes in breathing mechanics may be indicated by changes in tidal volume between breaths. System 20 may be configured to adaptively modify pacing parameters to return tidal volume to prescribed assist levels.

[0112] As mentioned above, differences or variability in tidal volume or breath-to-breath pressure can also be due to time-dependent fatigue of the stronger force-producing and fast-fatigable (type IIb) fibers. For example, FIG. 17A shows the natural progressive decline in percentage of type IIb fast-fatigable motor units contributing to force generation. Initially, type IIb motor units can generate much more 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 diaphragm contribution level shown in FIG. 17B. As shown diagrammatically in FIG. 18, initially, perhaps only 15% of all motor units in the phrenic nerve need to be recruited by system 20 to meet the prescribed force / pressure level of diaphragm contribution.

[0113] As shown in Figure 17, type IIb motor units tend to fatigue over time and produce less force, which causes the force (diaphragm contribution) to fall below the programmed level of the diaphragm contribution. To preserve the diaphragm contribution, the intensity of the 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%) to recruit more type I and type II motor units and produce the prescribed force.

[0114] Force drops again as type IIb motor units appear on the newly activated cross-section of the phrenic nerve and then fatigue. At this point, the pacing intensity is again increased 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, eventually recruiting up to 100% of the phrenic nerve motor units. Eventually, 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 should be understood that the stimulation increase can be a simple linear equation or a complex one, with weights assigned to the proportion of available fibers and their fatigue resistance. Force loss can be specifically attributed to fatigue of fast and fatigue-prone fibers using parameters such as 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 pressure-time index, expiratory time constant, EMG (and any derived parameters such as its power spectrum), and the ratio between slow and fast twitch amplitudes, can also be used to infer the changing state and determine the stimulation parameters to be modified.

[0116] In another embodiment, the closed loop control scheme may include using duos / trios in response to the slowing of contraction with fatigue of the diaphragm motor units. When fatigue is detected by the system 20, the stimulation pattern is automatically changed to include duos / trios or else to a lower stimulation frequency, since this form of stimulation is known in the art to optimize force production in fatigued / fatigued motor units. After the fatigued motor units regain their strength, the stimulation pattern can again be changed to a moderate stimulation frequency with or without duos. This closed loop scheme allows for continuous pacing of the diaphragm regardless of the onset or progression of fatigue, and also reduces the number of stimulation pulses delivered, protecting the muscle from potential injury that may be caused by overstimulation.

[0117] Returning to FIG. 14, a stimulation therapy is administered in block 110. The administration of the stimulation therapy includes generating a stimulation signal, such as a stimulation or gradient train. Depending on the outcome of block 108, the stimulation signal is generated with the original stimulation perimeter or with the stimulation parameters modified in block 108 described above. The timing of delivery of the stimulation gradient train is also determined in block 110. For example, the routine may determine the appropriate timing of phrenic nerve stimulation from a correlation with the actual breathing cycle of the ventilator 32. Generally described, the routine controls the timing of stimulation according to predefined rules based on parameter estimates from a breath detection algorithm or the like. The predefined rules may include whether stimulation begins any time before, during, or after the inhalation phase of the ventilator 32, as shown in FIGS. 11 and 12, or whether stimulation begins during the exhalation phase, as shown in FIG. 24.

[0118] For example, depending on the ventilator mode, the system 20 can trigger a pressure signal or an airflow signal. After the inspiratory / expiratory phase is determined to stimulate during the inspiratory phase, such as in block 104, the stimulation train can be initiated by triggering either the start of the expiratory phase followed by a delay, or the start of the inspiratory phase, as shown in FIG. 23. Triggering the start of the expiratory phase allows the stimulation to occur before the start of the inspiratory phase to maximize the diaphragm force during the inspiratory phase. In addition, stimulation during the expiratory phase can be achieved by triggering the start of the expiratory phase, or the start of the inspiratory phase with a delay, as shown in FIG. 24. Although it is preferable to use the start of inspiration or the start of expiration, it is also conceivable to use the end of the inspiratory / expiratory period. Furthermore, it is also possible to give a delayed stimulation, such that the stimulation begins, for example, in the middle of the inspiratory phase.

[0119] After the timing has been determined, the routine in block 110 delivers stimulation pulses to the stimulation electrodes 28 at the appropriate times for transfer therefrom. The routine returns to block 104 until the treatment period has ended or the clinician has stopped operation of the system 20.

[0120] In some embodiments, the system 20 can assist the clinician in determining an appropriate level of diaphragm contribution to be input into the system 20. In that regard, the diaphragm contribution can depend on the state of the patient's diaphragm. For example, for a patient with a maximum diaphragm output of only 750 mL, if the clinician intends to target a level of assistance of 500 mL, the clinician may unconsciously select a diaphragm contribution level that requires the delivery of a maximum stimulation charge, resulting in premature fatigue, etc. Given the current state of the patient's diaphragm, the clinician may wish to select a much lower percentage so that the stimulation charge is between the threshold charge and the supramaximal charge.

[0121] Thus, in some embodiments, in order to appropriately select the diaphragm contribution level, the state of the diaphragm and respiratory system is first evaluated by the system 20. In that regard, the system 20 is configured to perform one or more evaluations of the patient's diaphragm and / or respiratory mechanics. This evaluation determines the maximum diaphragm output (volume, pressure, or both), as well as other parameters such as the fatigue characteristics of the diaphragm, resistance, compliance, and relaxation characteristics of the respiratory system and its components. The evaluations can also be performed in synchrony with the ventilator 32 during or during periods of 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 operation of the ventilator 32 while the patient is connected to the ventilator 32, during which the diaphragm is paced alone. This series of pauses can be used manually by a clinician, or the system 20 can automatically identify and use natural pauses (end-inspiratory or end-expiratory pauses) that are part of the normal ventilator breathing cycle.

[0122] Generally described, after gas flow from the ventilator 32 is momentarily interrupted, the maximum static pressure generated by the diaphragm in response to supramaximal stimulation of the phrenic nerve to induce a diaphragmatic twitch, tilted contraction or tetanus is measured, as well as diaphragm relaxation characteristics during inspiration and expiration. In this assessment, the diaphragm may be paced alone at a preset duty cycle to evaluate diaphragm function with respect to its strength and endurance characteristics. Measurements and / or indices may be derived from data sensed by one or more sensors 48 and / or 50, including, but not limited to, maximum static / dynamic inspiratory pressures, inspiratory volumes, pressure-volume loop relationships, work of breathing, pressure-time products, pressure-time indices, EMG, maximum relaxation rate, and expiratory time constants. Diaphragm fatigue may be induced by continuous or intermittent stimulation of the phrenic nerve to assess endurance limits and detect the presence of low and / or high frequency fatigue. Because most of the calculated or derived parameters have wide normal ranges, a series of measurements spaced at times ranging from minutes to days can be performed on a patient with a pacing system to obtain a complete depiction of the evolving changes in the patient's diaphragm strength and endurance.

[0123] In some embodiments, knowledge-based algorithms can be used to monitor instantaneous and / or trend data of the monitoring signals, which can be evaluated to predict a patient's susceptibility to weaning and / or weaning over time. Such functionality can also be extended to allow clinicians to perform diaphragm assessment tests in the ICU as a standalone screening and / or confirmatory tool, since the method of transvascular pacing of the diaphragm allows clinicians to assess the true state of the diaphragm in the absence of confounding factors (such as reduced central vitality) that are typically associated with spontaneous breathing maneuvers.

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

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

[0126] FIG. 20A illustrates 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 ventilatory work is performed by the ventilator 32. The clinician can then adjust the ventilator settings to contribute 25% of the ventilatory work as tidal volume or pressure support, as shown in the lower graph of FIG. 20A. FIG. 20B illustrates 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 ventilatory work is performed by the ventilator 32. The clinician can then adjust the ventilator settings to contribute 75% of the ventilatory work as tidal volume or pressure support, as shown in the lower graph of FIG. 20B. Alternatively, PPMV can be set in a mode in which the remaining portion of the prescribed assist level is automatically determined and adjusted by the ventilator between or within breaths (e.g., a pressure-adjusted volume control mode). In some embodiments, the system 20 can also calculate or otherwise obtain stimulation characteristics corresponding to the diaphragm contribution, hi another embodiment, the clinician can input data representing these stimulation characteristics.

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

[0128] An example of a routine for measuring changes in diaphragm status without removing the patient from the ventilator 32 is shown in Figure 22. As with the diaphragm assessment described above, a series of approximation routines can be used in some embodiments to determine optimal parameters for stimulation to the patient.

[0129] As best seen in FIG. 22, the routine 200 begins with the clinician providing initial system parameters, which may include maximum allowable stimulation parameters. The stimulation parameters may be provided as a predefined stimulation train, where the duration is fixed so that the stimulation train is fully defined by the user using the methods described above, or as a stimulation train where the number of pulses and train duration are based on the detected ventilator inspiration time. The routine then executes a breath detection algorithm to detect the inspiration and expiration phases using flow / pressure data sensed by the breath sensor 50. In addition, flow and pressure data for one or more breaths without stimulation are collected and stored.

[0130] Depending on the ventilator mode, the system 20 can trigger a pressure signal or an airflow signal. After the inspiratory / expiratory phase is decided to stimulate during the inspiratory phase, the stimulation train can be started by triggering either the start of the expiratory phase followed by a delay, as shown in FIG. 23, or the start of the inspiratory phase. Triggering the start of the expiratory phase allows the stimulation to occur before the start of the inspiratory phase to maximize the diaphragm force during the inspiratory phase. In addition, stimulation during the expiratory phase can be achieved by triggering the start of the expiratory phase, or the start of the inspiratory phase with a delay, as shown in FIG. 24. Although it is preferable to use the start of inspiration and the start of expiration, it is also conceivable to use the end of the inspiratory / expiratory period. Furthermore, it is also possible to give a delayed stimulation, so that the stimulation starts, for example, in the middle of the inspiratory phase.

[0131] Flow, volume, and / or pressure data, or derived parameters thereof, for at least one breath with stimulation are recorded. If multiple breaths of information are recorded with and without stimulation, the data can be averaged together. The flow / volume / pressure data collected with stimulation is then subtracted from the flow / volume / pressure data collected without stimulation. This difference, calculated as an area (and illustrated as the darkened area), can be used as a relative measure of the force generated by the diaphragm and is shown in FIG. 26. In the case of pressure-controlled breaths, the difference in volume (area under the flow curve) is used as the measurement. In the case of volume-controlled ventilators, the area under the pressure graph is used as the measurement.

[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., no interference with ventilator operation or ventilator disconnection) and can evaluate diaphragm recruitment in response to varying (decreasing or increasing) stimulation charge. When executing the evaluation routine 300, the system 20 can deliver a low frequency stimulation (e.g., 1 Hz to 5 Hz) during one or more quiet expiration periods to elicit an unfused diaphragm contractile response in the form of a single twitch. The delivered charge can be progressively increased to build a complete neural assist curve for each intravascular location, and the operator can specify over how many respiratory cycles this stimulation is delivered. The system 20 can analyze this stimulation and response information to algorithmically estimate the best electrode location to stimulate one or both phrenic nerves using the least amount of charge (highest efficiency). During this evaluation routine, the system 20 may also gather information regarding the relationship between stimulation train characteristics and the corresponding diaphragmatic response, including diaphragmatic output (volume, pressure, or both). Some stimulation parameters that may be obtained include, but are not limited to, the threshold pulse width and supramaximal pulse width required to recruit each phrenic nerve from the appropriate intravascular electrode location.

[0133] As illustrated in Figure 28, the stimulation charges of the routine 300 can be programmed to occur periodically during a baseline flow / volume period, which may occur at the end-expiratory pause of the ventilator breathing cycle, sometimes referred to as the end-expiratory delay. 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 condition for comparable results. This provides a standardized baseline for comparing diaphragm twitch responses and can guide intravascular electrode placement.

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

[0135] Using volume data in some embodiments is one technique, but this does not preclude using other measures 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, the system 20 can calculate respiratory system relaxation characteristics, such as the expiratory time constant (i.e., the time required to exhale a certain percentage of 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 manually disable the system and to select the duration of the end-expiratory pause as a percentage of the measured expiratory phase duration or as an absolute value.

[0136] Returning to Figure 27, the evaluation routine 300 will now be described in some detail. The routine 300 begins at block 302 with the clinician providing initial system parameters or accepting internal default values, which may include characteristics of a low-level initiation stimulation signal, a maximum stimulation level, an estimated duration of the end-expiratory pause, one or more ventilator parameters, etc. In some embodiments, the characteristics of the low-level initiation stimulation signal are based on the estimated duration of the end-expiratory pause.

[0137] The breath detection algorithm described above can then be used in block 304 to synchronize the delivered stimulation with the end-expiratory pause of the ventilator 32. For example, as shown in FIG. 28, the breath detection algorithm can be used to identify periods of interest during the respiratory cycle during which stimulation can be delivered. Because the diaphragm is a skeletal muscle, its force output varies with its length, as indicated by its length-tension relationship. It is therefore beneficial to stimulate the diaphragm at approximately its resting length, as this provides a standard baseline for comparing diaphragm twitch responses. The resting length of the diaphragm is reached at the end of every expiratory phase, when the lungs reach their functional residual capacity. Thus, inspiration and expiration volumes can be monitored to non-invasively estimate when the lungs reach functional residual capacity. In addition, signals, such as pressure signals in the form of intraesophageal or intrathoracic pressures, from one or more of sensors 48 and / or sensor 50 can be used to confirm that the lungs have reached functional residual capacity.

[0138] Based on the aforementioned monitored parameters, a determination is made at block 306 as to whether the patient's lungs are returning to functional residual capacity as the ventilator performs a breathing cycle. If functional residual capacity is determined to be reached, the system 20 provides an initiation stimulus signal at block 308 and then monitors and measures the diaphragmatic response to the provided stimulus at block 310. Signals that may be monitored and measured to quantify the diaphragmatic response may include, but are not limited to, EMG, airway pressure, airway flow, intrathoracic pressure, intrathoracic pressure, central venous pressure, thoracic and abdominal motion, various patient impedances, and the like.

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

[0140] Because functional residual capacity can change over time due to factors such as exogenous positive end-expiratory pressure (PEEP) or intrinsic positive end-expiratory pressure, the system can also use a validation check to ensure that functional residual capacity (and therefore diaphragm rest length) is not changing from breath to breath. One means of performing this validation is to analyze trend data for end-expiratory volume before stimulating the diaphragm.

[0141] The next mode of operation that may be performed by an embodiment of the system 20 includes a pacer-initiated breathing mode. FIG. 30 illustrates an example of a routine 500 executed by the system 20 to perform one or more functions including the pacer-initiated breathing mode. In that regard, many mechanical ventilators have an assist / assist 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 may be programmed to trigger the ventilator 32 operating in an assist mode to mimic a spontaneous effort by the patient by using a stimulus (and the resulting response from the diaphragm) shown at "D" in FIG. 31. The ventilator 32 responds to this trigger signal / event and delivers a breath to the patient shown at "B" in FIG. 31 (based on parameters set by the clinician). In effect, the system 20 drives the delivery of a breath from the ventilator 32 shown at "C" in FIG. 31 (as opposed to the ventilator-initiated pacing mode discussed above). 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 rate of pacing by programmable parameters such as breath rate (breaths per minute), skipped breaths, and sigh breaths. Similarly, the pacer-initiated breathing mode can also include one or more of adaptive functions, closed loop control, diaphragm evaluation, and the set of approximation functions described above with respect to the ventilator-initiated pacing mode are also applicable to this mode.

[0142] In a pacer-initiated ventilation mode, the system 20 can use feedback to ensure adequate diaphragmatic contribution. Some ventilator modes that are suitable for this embodiment include pressure supported ventilation (PSV), pressure regulated volume control (PRVC), proportional assist ventilation (PAV), and adaptive assist ventilation (ASV).

[0143] Embodiments of the system 20 can also be operated in an autonomous mode, or A-mode. A-mode is a life support mode that can operate independently of the ventilator 32. FIG. 32 illustrates an example of a routine 600 executed by the system 20 to perform one or more functions including the autonomous mode. In that regard, the A-mode 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, which may include, but are not limited to, central venous pressure, mixed venous oxygen saturation, heart rate, and exercise activity level. The A-mode can provide adjustable diaphragmatic pacing for patients who have no, some, or all spontaneous breath retention and require assisted ventilation, automatically adapting to the patient's physiological needs and changed activity level as needed.

[0144] A-Mode may be a life-supporting mode, which may or may not be used in this capacity (i.e., it may be connected to a back-up ventilator). For example, A-Mode may be applicable to patients who are permanently dependent on a mechanical ventilator or who otherwise require continuous pacing from system 20.

[0145] In contrast to the previously described embodiments of system 20 for performing the Pacer-Initiated Ventilation Mode and the Ventilator-Initiated Pacing Mode, the embodiment of system 20 performing the A-mode may be fully implanted under the skin in the upper chest of a patient. In this regard, system 20 may be powered from a power storage source, such as a primary or rechargeable implantable battery, and may be integrated with other implantable devices that support the patient's cardiac or other functions.

[0146] As shown in the embodiment of Fig. 32, system 20 operating in A-mode includes closed loop operation to pace the diaphragm autonomously. In this mode, any patient response signal (feedback) may be utilized to help indicate the need for pacing, including, but not limited to, oxygen saturation, end tidal CO2 (EtCO2), airflow, heart rate, motion detecting accelerometer signals, etc. Pacing continues to be provided in A-mode, with algorithms used to detect and / or modify the physiological response signals to determine if changes in stimulation pattern, frequency, respiration rate, intensity, type, and / or shape characteristics are necessary to elicit the expected response.

[0147] The principles, representative embodiments, and modes of operation of the present disclosure have been described above. However, the aspects of the disclosure that are to be protected should not be construed as being limited to the particular embodiments disclosed. Moreover, the embodiments described herein are to be considered as illustrative and not restrictive. It is to be understood that variations and modifications may be made by others and equivalents may be used without departing from the spirit of the present disclosure. Accordingly, it is expressly intended that all such variations, modifications, and equivalents are included within the spirit and scope of the present disclosure as claimed.

Claims

1. In the stimulation system, a stimulator for delivering stimulation signals to electrodes located under the patient's skin; a sensor for acquiring diaphragm output data; 1. A processor comprising: calculating the work of breathing based on the diaphragm output data; Calculating a desired electrical stimulus based on the calculated work of breathing; and the processor for delivering the calculated desired electrical stimulation to a phrenic nerve to at least partially activate the patient's diaphragm.

2. The system of claim 1 , wherein the diaphragm output data includes a volume measurement and a pressure measurement.

3. The system of claim 1 , wherein the work of breathing comprises the work performed by the patient during one or more phases of a respiratory cycle.

4. The system of claim 1 , wherein the work of breathing comprises the work done by the patient's diaphragm.

5. The system of claim 1 , wherein the sensor obtains the diaphragm output data by sensing airflow generated by the patient.

6. The system comprises: acquiring diaphragmatic output data using said sensor for a number of breaths taken by said patient; averaging the diaphragm output data to generate averaged diaphragm output data; and determining an average work of breathing performed over the plurality of breaths based on the averaged diaphragm output data. The system according to any one of claims 1 to 5, wherein the work of breathing is determined by:

7. The system of any one of claims 1 to 5, wherein the sensor is connected to a breathing circuit of a mechanical ventilator.

8. 6. The system of claim 1, wherein the system determines when inspiration of a given breath is occurring based on the diaphragm output data and delivers the electrical stimulation during the determined inspiration.

9. The breath is a breath in which the patient is receiving respiratory assistance from a ventilator. The system of claim 8.

10. The processor further comprises: Determine maximum diaphragmatic output, 10. The system of claim 9, further comprising: adjusting the ventilator based on the maximum diaphragmatic output.

11. The system of claim 8 , wherein the system terminates the electrical stimulation before the onset of a subsequent breath.

12. The system of claim 1 , wherein the processor further modifies the desired electrical stimulation signal based on whether a measured parameter is outside a preselected target range.

13. The system of claim 1 , wherein the electrodes are supported on a catheter configured to be inserted into the patient's vascular system.

14. 14. The system of claim 13, wherein the catheter supports a plurality of electrodes including the electrode, the plurality of electrodes including a first group of electrodes positioned adjacent to a left phrenic nerve and a second group of electrodes positioned adjacent to a right phrenic nerve.

15. The processor further comprises: delivering a plurality of electrical pulses from the electrodes to stimulate the phrenic nerve; determining a diaphragmatic response corresponding to said plurality of electrical pulses; The system of claim 1 , further comprising: evaluating a relationship between a characteristic of a first plurality of electrical pulses and the diaphragmatic response.

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