Respiratory rectification

ES 2 826 328 T3

DESCRIPTION

Respiratory rectification

Background

The present disclosure relates to a system for treating breathing disorders. US 2007/118183 A1 discloses a system for this purpose.

In humans, gas exchange is accomplished by rhythmic inflation and deflation of the lungs. During respiratory movements, the lung is passive and its volume is determined by the size of the thorax, which in turn depends mainly on the activity of the intercostal and diaphragm muscles.

The vertical movement of the diaphragm is approximately 1.5 cm during quiet breathing and can be as high as 7 cm in deep breathing. A 1 cm lowering of the diaphragm will increase the thoracic capacity by approximately 300 ml and cause a corresponding volume of air to enter the lungs. Thus, movements of the diaphragm can be responsible for approximately 60-80% of lung distention and total air breathed.

A respiratory control center in the brain controls the respiratory muscles. The respiratory muscles consist of the respiratory pump (diaphragm and intercostal muscles) and muscles of the airways. The nerve signals that travel to the respiratory muscles constitute the central respiratory drive. While the diaphragm is the main source of power for the respiratory pump, the function of the airway muscles is to keep the airway open. Without a central neuronal drive, the airways can close or partially occlude.

During sleep, respiratory control is unconscious and is governed by metabolic demand (mainly the need to remove CO2 from the blood). In all humans, the central neural drive for the respiratory pump and airway muscles during sleep is reduced compared to a waking state. In the presence of a mild pathology, the resistance of the airways to the flow of air can be increased during sleep resulting, for example, in snoring. In extreme cases, the airways can close completely resulting in obstructive sleep apnea (OSA). In some cases, dysregulation of central control can result in periodic breathing and severe disease that can damage multiple organs.

Central sleep apnea (CSA) is a form of periodic breathing characterized by an oscillating central respiratory drive. CSA can be characterized by a typical fluctuating respiratory pattern composed of alternating apneas and hyperpneas (periods of hyperventilation), historically termed Cheyne-Stokes respiration (CSR).

Obstructive sleep apnea (OSA) is characterized by instability of the upper airways. A closed airway prevents or reduces inspiration despite continued or increasing respiratory effort. A common pattern of OSA in the general population is characterized by periodic excitations that result in abrupt opening of the airways.

The inventors have discovered that, in some patient populations, such as those with congestive heart failure (CHF) for example, it is difficult, if not impossible, to separate the underlying mechanisms of OSA and CSA. A purely core CSR pattern is rare. The usual presentation of periodic breathing in patients with CHF may consist of alternating respiratory events that may include hyperpneas, hypopneas, and central, obstructive, and mixed apneas. There is significant overlap and most patients experience varying degrees of both central and obstructive events. In fact, it is believed that the oscillating central respiratory drive can lead to increased resistance or closure of the upper airways.

After an extensive series of experiments, the inventors found that effective treatment of many cases of periodic breathing required addressing the central neuronal drive to breathe as well as airway problems. Due to the relationship between respiratory pump muscles and airway muscles, the inventors wished to modulate the intrinsic respiratory activity of the brain to affect both aspects of respiration. The respiratory control center of the brain is located in the medulla of the brain and is not directly accessible to modern neuromodulation technologies. Therefore, the inventors were forced to investigate neuronal inputs to the brain that govern the behavior of the respiratory control center.

The brain's respiratory control center receives inputs from chemoreceptors in the arterial vasculature (in the aortic arch, carotid bodies, and blood vessels in the brain itself) and from mechanoreceptors such as the respiratory pump muscles, lung stretch receptors in the lung and intercostal stretch receptors. It is known that altering the input to the brain from chemoreceptors by having the patient breathe in some carbon dioxide can control periodic respiration.

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The phrenic nerves control the movement of the diaphragm, which in turn can lead to the activation of series of neuronal inputs to the brain, for example by stretching various innervated tissues in the thorax. The Hering-Breuer reflex is powerful neuronal feedback from stretch receptors in the lung to the brain. When the lung is inflated and stretched, the respiratory center of the brain suspends the breath drive. The synchronization of respiration with external stimuli in sleeping humans is believed to involve the Hering-Breuer reflex as well as other neuronal inputs.

The technology the inventors chose for research was phrenic nerve stimulation. A form of phrenic nerve stimulation known as "electrophrenic ventilation" or "diaphragmatic electrostimulation" has been used for many years to replace intrinsic respiration. The physiology of respiratory electrostimulation is simple. The phrenic nerve is stimulated to control respiration by slightly hyperventilating the patient. The consequent reduction in the concentration of carbon dioxide in the blood is detected by the respiratory control center of the brain and substantially all neuronal output from the center (central respiratory drive) is stopped. A patient, subjected to electrostimulation in this way, may not experience respiratory disturbances while undergoing electrostimulation but becomes temporarily dependent on phrenic "electrostimulation" for ventilation and gas exchange.

Such phrenic electrostimulation has been used to treat paraplegia and central congenital hypoventilation syndrome in children since the 1960s and successfully prevented death by substituting an artificial impulse for natural respiration. By controlling respiration, such electrostimulation suppresses the intrinsic central respiratory drive. Although it eliminates the oscillations of the breath drive, it can also remove the drive to keep the airway open. In patients with central congenital hypoventilation syndrome, this limitation can be overcome by tracheostomy (a surgical procedure in the neck to open a direct airway through an incision in the trachea). A tracheostomy is unacceptable in patients with periodic breathing.

In contrast, embodiments according to the present disclosure apply stimulation only to a phrenic nerve at a constant rate that, in some embodiments, is slightly below the intrinsic rate of the patient. These embodiments may result in the synchronization of the patient's central respiratory activity rather than the suppression of the intrinsic impulse. When applied during periodic respiration in sleeping individuals, and delivered within a particular range of stimulation parameters, this form of phrenic nerve stimulation often resulted in restoration of normal respiratory rhythm, was sustainable, and was well tolerated during natural sleep.

In some embodiments according to the present disclosure, the stimulation results in rhythmic contractions of a hemidiaphragm enervated by the nerve stimulated by the stimulated nerve and consequent rhythmic pulmonary inflates. The patient's intrinsic breathing rhythm is modulated by stimulation, becoming more regular and showing less periodicity. The improvement in respiration is believed to be achieved through the mechanism of lung distension and synchronization of neurons in the respiratory center of the brain, among other mechanisms, rather than through the control of respiration itself. Spontaneous respiration and central respiratory drive are preferably preserved, thus resulting in the benefit of maintaining airway muscle tone and natural blood gas regulation.

Another embodiment according to the present disclosure relates to monitoring and controlling diaphragmatic pacing and pacing timing. This embodiment is based on the assumption that when pacing synchronizes respiration, the spectral power of the respiratory signal in the immediate range of the pulse frequency will be significantly higher than in other frequency bands. In one embodiment, a ratio of total variance of the breath signal that lies within the narrow band centered on the pacing rate to the total variance in the wider respiratory rate band can be calculated. The value of this ratio can be expected to increase in proportion to the timing of respiration by stimulation, thus allowing a guided and calibrated therapy based on the effect of stimulation on actual respiration. Two exemplary calculation methods for such a ratio are disclosed herein: the spectrum method and the histogram method. It should be understood that these methods are not the only ways to determine the timing or efficiency of nerve or muscle capture by frequency analysis, and other methods will occur to those of skill in the art upon reading this disclosure.

The inventors observe occasional regularization of the respiratory rhythm and resolution of both central and obstructive apnea during unilateral phrenic stimulation. The inventors found that phrenic stimulation prevents and corrects the intrinsic periodicity of respiration in patients who frequently show oscillatory breathing during sleep. The inventors observe that the patient's breathing, previously highly irregular, gradually synchronizes to the rhythm of the phrenic stimulation and follows it if the stimulation frequency is changed. The inventors have also observed a fixed and repetitive coupling between external stimulus and neuronal inspiratory activity in the respiratory control center of the brain. The inventors confirmed that the patient's breathing was synchronized, and in fact spontaneous, by making the following observations:

(1) When stimulation stopped abruptly, the patient did not stop breathing. In some cases, patients continued to breathe "as if still receiving stimulation" following signals that were no longer present for several minutes before returning to the pre-stimulation pattern.

ES 2 826 328 T3 (2) Since only one phrenic nerve was stimulated, the second lung was free to inflate and deflate without the direct influence of the stimulation. The inventors confirmed the independent movement of the unstimulated lung by independent measurements of transthoracic impedance.

(3) Often, patients were observed to insert or intersperse small spontaneous breaths between breaths synchronized to stimulation, thereby confirming that the central respiratory drive remained active. These interleaved breaths did not interfere with the timing pattern.

Stabilization of blood gases and the elimination or reduction of intermittent hypoxia and excitations associated with hyperventilation by synchronization with phrenic stimulation is believed to improve airway tone. Hypoxia is an exceptionally strong stimulus to hyperventilate, as is the neurological arousal that often follows hypoxia. The intensity of hyperventilation that follows intermittent hypoxia determines the subsequent reduction of CO2 in the blood that results in the withdrawal of neuronal stimulus to both the respiratory pump muscles and the airway muscles. The opposite also is true. The reduction of hypoxia and subsequent hyperventilation aggravated by hypoxia should help maintain the respiratory drive and maintain airway neuronal muscle tone after transient hyperpnea has ended.

Another way that CSA is thought to reduce upper airway stability and induce OSA is by promoting periods of hypopnea. During hypopnea, the activity of both the respiratory pump muscles (eg diaphragm) and the upper airway dilator muscles (eg genioglossus) is reduced. Thus, a fluctuating pattern of central respiratory drive in an individual who has an upper airway prone to closure can result in obstructive apnea / hypopnea during periods of hypopnea due to upper airway hypotonia (low muscle tone). It is reasonable to assume that the opposite is also true. Reducing hypopnea in CSA patients will help stabilize the airways by increasing the tone of the airway muscles.

In the context of this disclosure, hypopnea broadly refers to a transient reduction in air flow (while sleeping) lasting at least 10 seconds due to transient shallow breathing, or abnormally low respiratory rate. In the medical literature, breathing that is too shallow (hypopnea) or too slow (bradypnea) is sometimes differentiated. Hypopnea is less serious than apnea (which is a more complete loss of airflow) but can still result in a reduced amount of air movement into the lungs and can cause blood oxygen levels to drop ( hypoventilation).

There is no firm scientific consensus on the narrow or quantitative definition of hypopnea and it is understood that many definitions are often used in the scientific literature and can be applied.

For example in their research, which served as the basis for this disclosure, the inventors used transient reduction in respiration (air flow) by> 30% for a duration of 10 to 60 seconds accompanied by detectable oxygen desaturation (4%) as Quantitative "technical" definition of hypopnea. Within the narrow scope of this quantitative definition, hypopnea and transient hypoventilation are equivalent for all practical purposes.

When broadly defined, hypoventilation is the state in which a reduced amount of air enters the alveoli in the lungs, resulting in reduced levels of oxygen and / or increased levels of carbon dioxide in the blood. Hypoventilation can also be defined broadly, and perhaps better, as breathing that is not adequate to meet the body's needs. Hypoventilation may be due to hypopnea or reduced lung function. Hypoventilation can be transient (as a result of hypopnea) or sustained due to various pathologies such as congenital disease, chronic obstructive pulmonary disease (COPD) or obesity.

Periodic lung inflation plays an important role in maintaining neuronal sympathetic-parasympathetic balance, heart rate, and regulation of blood pressure. As early as the 1940s, many of these physiological interactions were traced back to neuronal feedbacks that signal lung expansion to the autonomic nervous system. The role of the autonomic nervous system in the homeostasis of the organism is particularly important during sleep. These beneficial feedbacks have been classified according to the inflation of the lung.

The importance of neuronal feedbacks from the stretch receptors in the lungs to the multiple centers in the brain that control cardiovascular activity can best be demonstrated by the so-called respiratory sinus arrhythmia. Respiratory sinus arrhythmia (RSA) is a change in heart rate that occurs in sync with respiration, whereby the RR interval on an ECG shortens during inspiration and lengthens during expiration. Although RSA has been used as an index of cardiac vagal function, it is also a physiological phenomenon that reflects universally observed respiratory-circulatory interactions among vertebrates. Studies have shown that the efficiency of lung gas exchange is improved by RSA, suggesting that RSA may play an active physiological role. The

ES 2 826 328 T3 coincident synchronism of alveolar ventilation and its perfusion with RSA within each respiratory cycle can reduce energy expenditure by suppressing unnecessary heartbeats during expiration and ineffective ventilation during ebb of perfusion. RSA or heart rate variability in sync with respiration is a biological phenomenon, which can have a positive influence on gas exchange at the lung level through efficient respiration / perfusion matching.

The inventors observed an increase in RSA when CHF patients were treated according to embodiments of the invention. It is reasonable to expect that other benefits such as dilation of blood vessels and reduction of malignant arrhythmias will follow.

Phrenic or diaphragm stimulation according to embodiments of the present disclosure can expand respiratory or lung volume to combat the effects of hypopnea. Pacing is also expected to result in sustained lung expansions as opposed to the fluctuating pattern found in CSA. Additional airway tone benefit can be expected from these improvements. In patients with significant CSA, the upper airways are closed and the resulting OSA may be secondary to the withdrawal of neuronal and mechanical stimulus to the airways caused by reduced parasympathetic activation and reduced lung inflation during episodes of apnea / hypopnea. central.

A clinical benefit can be derived from synchronization of the intrinsic respiratory rhythm by stimulation. Increased lung volume, stabilized blood gas composition, and reduced hypoventilation all suggest an improvement in airway dynamics in addition to primary correction of central respiratory instability.

The upper airway dilator muscles play an important role in maintaining the patency of the airways. Many of the pharyngeal dilator muscles are known to demonstrate inspiratory phasic activity, the onset of which precedes diaphragmatic activity. That is, the airway muscles contract in phase with respiration slightly earlier than the respiratory pump muscles, thereby "preparing" the pharyngeal airway for the development of negative pressure during inspiration.

The best studied pharyngeal muscle is the genioglossus. The genioglossus receives input from the brain's respiratory control center (or more precisely from the brainstem's central respiratory pattern generator) located in the medulla oblongata. The hypoglossal nerve activates the genioglossal nerve, and the hypoglossal nerve has been found to activate 50-100 ms earlier than the phrenic nerve in healthy patients.

Chemoreceptor inputs are also important in influencing hypoglossal motor nerve output. A low level of CO2 in the blood (hypocapnea) reduces activation and a high level of CO2 (hypercapnea) increases it. Therefore, it may be useful for any treatment of periodic breathing to avoid hypocapnea and the reduction in airway muscle activation that accompanies hypocapnea.

Embodiments according to the present disclosure can be used to treat periodic breathing in sleeping patients, but can also be used to regulate breathing in people at rest with ischemic heart disease, heart failure, hypertension, COPD, and other conditions in which improved breathing efficiency results. advantageous.

In one embodiment according to the present disclosure, a measured frequency zone is defined based on measured physiological signals associated with intrinsic contraction of a muscle. A stimulation frequency zone is defined based on the stimulation frequency of an electrical pulse generator configured to stimulate the muscle or a nerve associated with the muscle at a frequency other than the intrinsic frequency. The muscle or a nerve associated with the muscle is stimulated and the impact of the stimulation is determined by comparing the measured power of a matrix of signals found within the measured frequency zone with the measured power of the matrix of signals found within the stimulation rate zone. In variations of this embodiment, the physiological signal is a representative signal of respiration. In another embodiment, the muscle is a diaphragm muscle. In yet another embodiment, the measured frequency zone comprises a range of frequencies close to the respiration rate of a patient.

In another embodiment according to the present disclosure, a system for electrical stimulation of a nerve or muscle includes an electrical pulse generator that supplies energy to stimulate a muscle at a first frequency, the first frequency being different from a second frequency at which it is used. it inherently contracts the muscle. The system of this embodiment also has a sensor that detects physiological activity indicative of contraction of the stimulated muscle and an electronic memory for storing an array of data generated by the sensor over a period of time. A frequency analyzer analyzes the data matrix to determine the power distribution along a frequency band for detected physiological activity, and a system circuitry can compare the power in a band close to the stimulation frequency with the total power along the frequency band for the detected physiological activity.

In another embodiment according to the present disclosure, a system for electrical stimulation of a nerve or muscle includes an electrical pulse generator that supplies energy to stimulate a muscle at a first frequency, the first frequency being different from a second frequency at which it is used. inherently contracts the

ES 2 826 328 T3 muscle. The system of this embodiment also has a sensor that detects physiological activity indicative of contraction of the stimulated muscle and an electronic memory for storing an array of data generated by the sensor over a period of time. A frequency analyzer analyzes the data matrix to determine the power distribution along a frequency band for the sensed physiological activity and a system circuitry can compare the power in a band close to the stimulation frequency with the power total across the frequency band for detected physiological activity. In this embodiment, the circuitry can increase the energy delivered by the pulse generator if the ratio of the power in the band near the stimulation frequency to the total power is below a threshold.

In another embodiment according to the present disclosure, a system for treating breathing disorders includes an electrical pulse generator that can provide electrical stimulation signals to a phrenic nerve or diaphragm of a patient at a predetermined signal frequency. This embodiment has a respiration sensor that can detect a signal representative of the patient's respiration and a rate comparator that compares the power density of the frequency distribution of detected respiration signals along a pacing frequency band with the power density of detected breathing signals along a respiratory frequency band The system includes a set of power adjustment circuitry that adjusts the power of the electrical stimulation signals provided by the electrical pulse generation based on the comparison of power densities. In various embodiments, the power adjustment circuitry can adjust the stimulation current, the stimulation voltage, the frequency of the pulses in a pulse train, the pulse duration of the pulses in a pulse train, or other parameters. .

In yet another embodiment according to the present disclosure, a phrenic nerve or diaphragm is stimulated at a rate below an intrinsic respiration rate. Stimulation is delivered at an intensity sufficient to synchronize breathing while leaving the intrinsic drive to breathe intact. In some embodiments, the respiratory drive manifests as a 2: 1 timing, in others as spontaneous breathing of an unstimulated lung, in others as smaller breaths interspersed between synchronized breaths, and in others as periodic activation of airway muscles.

In another embodiment according to the present disclosure, breathing disorders are treated by detecting a signal representative of a patient's respiration and performing a frequency analysis of the signal representative of respiration over a range of frequencies compatible with the breathing. This embodiment includes the steps of determining an intrinsic respiration rate or rate and stimulating a patient's hemidiaphragm at a rate different from the respiration rate. In this embodiment, a frequency analysis of the respiration signal is performed during stimulation. A capture index is determined by dividing the power distribution in a frequency range close to the pacing rate up to the power of the frequency range compatible with respiration to determine a capture index. Stimulation parameters are modified based on the calculated capture index. In some embodiments, the representative signal for respiration may be transthoracic impedance. In some embodiments, the stimulation rate is less than the intrinsic respiration rate.

In another embodiment according to the present disclosure, breathing disorders are treated by detecting a signal representative of a patient's respiration and performing a frequency analysis of the signal representative of respiration over a range of frequencies compatible with the with breath. This embodiment includes the steps of determining an intrinsic respiration rate or rate and stimulating a patient's hemidiaphragm at a rate different from the intrinsic rate of respiration. In this embodiment, a frequency analysis of the respiration signal is performed during stimulation. A capture index is determined by dividing the power distribution in a frequency range close to the pacing rate up to the power of the frequency range compatible with respiration to determine a capture index. Stimulation parameters are modified based on the calculated capture index. In some embodiments, the stimulation power is increased if the capture rate is below a certain threshold. In some embodiments, the stimulation power is reduced if the capture rate is above a certain threshold.

Brief description of the drawings

Figure 1 is a waveform of respiration data from an untreated patient.

Figure 2 is a waveform of the respiration of the patient of Figure 1 during therapy according to embodiments of the invention.

Figure 3 is a spectral graph of the respiration data presented in Figure 1.

Figure 4 is a spectral graph of the respiration data presented in Figure 2.

Figure 5 is a graph of experimental data related to respiratory disorders in a patient treated according to embodiments of the invention.

Figure 6 is a waveform of respiration and pacing data associated with a patient therapy.

ES 2 826 328 T3 according to embodiments of the invention.

Figure 7 is a control flow diagram according to embodiments of the invention.

Figure 8 is a schematic view of a patient and therapy device according to embodiments of the invention.

Detailed description

Figure 1 is a waveform of respiration data from an untreated patient. The waveform represents 60 seconds of data acquired during the time the patient was asleep. Profile 101 represents normal (resting) breathing for this patient. Profile 101 was acquired at 10:42 pm just before the patient received therapy. Profile 101 represents the flow of air into and out of the lungs of the patient monitored with a flow meter (thermal sensor). At this time, the patient is not showing periodic breathing or apnea and the patient is breathing regularly at 24 breaths per minute (0.4 Hz).

Figure 2 is a waveform of the respiration of the patient of Figure 1 during therapy according to embodiments of the invention. This waveform also represents 60 seconds of data acquired when the patient was asleep. The patient has CSA and was treated using transvenous stimulation of the right phrenic nerve. Profile 103 represents trains of stimulation pulses. The pacing pulse trains were delivered at a constant rate of 18 per minute (0.3 Hz pulse rate), in this case below the patient's native respiration rate of 24 breaths per minute. Each train of pulses has a duration of 1.67 seconds. During the application of the pulse train, the right phrenic nerve was stimulated and the muscles of the right hemidiaphragm were contracted (stimulation phase 104). Each pulse train is followed by the relaxation phase 105 which also has a duration of 1.67 seconds in this example. During the relaxation phase, the phrenic nerve is not stimulated. Thus, stimulation pattern 103 represents 50% duty cycle stimulation (50% inspiration - 50% expiration). Other ratios or duty cycles can be used to achieve the objectives of the invention.

Each pulse train 104 is composed of series of individual pulses (not shown) supplied by a pulse generator. The pulse generator can be external or implanted. In this example, the pulses have a duration of 150 μs (microseconds) and are applied at a frequency of 20 Hz. The pulse generator in this example applied pulses in a pre-programmed, controlled manner, to achieve a pre-peak current amplitude. 4.9 mA programmed. To increase patient comfort, the pulse electrical current amplitude within the pulse train can be gradually increased, kept constant, and then gradually decreased within the same pulse train. Other forms of pulse train can be used to elicit desired contraction and relaxation responses of the diaphragm muscle without departing from the scope of this disclosure.

Profile 102 represents the patient's respiration during stimulation therapy. Similar to Profile 101 in Figure 1, it consists of individual breaths monitored by a flow meter. Each breath consists of an inspiration phase 106 and an expiration phase 107. It can be seen that there are mainly large breaths 108 and some smaller breaths 109. Large breaths are locked in phase with the pacing pulses 103 and the patient's breath can be said to be in sync with the pacing. These large breaths appear at the same rate as the pacing pulse train rate of 18 per min (0.3 Hz).

When only large breaths appear in series, they indicate 1: 1 timing (one breath for each train of pacing pulses). When small breaths appear, they can appear in various ways. In some cases, small breaths are sandwiched between large breaths at a rate that generally corresponds to the spontaneous breath rate of 24 breaths per minute (0.4 Hz). In some cases, small breaths only appear occasionally as required by metabolic demand. In other cases, the periods of interleaved breaths correspond to a 2: 1 timing (two breaths for each train of pacing pulses). In all cases, the existence of small spontaneous or synchronized 2: 1 breaths supports the deduction that although the breath is synchronized in this way, the respiratory control center is still active.

Although the breaths in profile 102 appear at the same base rate as pacing 103, they are not necessarily exactly in sync with pacing. Inspiration 106 may start at a different delay time after the start of the stimulation pulse trains 104 and, under certain circumstances, may even precede the start of the corresponding stimulation pulse train.

In the embodiment depicted in Figure 2, stimulation is applied at a rate somewhat lower than the spontaneous breathing rate at rest (in this example: 18 vs. 24 / min). Stimulation can synchronize spontaneous breathing but is not a substitute for it. Synchronization is demonstrated by the variable time delay and phase angle between the pacing pulse trains and the inspiratory effort of the patients. Additional evidence of timing is the periodic occurrence of 2: 1 and 1: 1 timing or other small breaths that are not in sync, showing that the respiratory drive is not suppressed, but is in sync.

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Figure 3 is a spectral graph of the respiration data presented in Figure 1. Periodic waveforms such as respiration waveforms illustrated by Figure 1 can be analyzed using various frequency domain methods, the most common of which are what is the spectral analysis.

Figure 3 shows the patient's normal spontaneous breathing spectrum illustrated by profile 101 in Figure 1. Such a spectrum can be obtained by performing fast Fourier transform (FFT) on 2-3 minutes of digitally acquired respiratory signal data (in this example, air flow). The spectrum can be a power spectrum, a power density spectrum, or a magnitude spectrum. The power spectrum can also be considered to provide which frequencies contribute the most to the variance of the signal. The greater the amplitude, the greater the variance. This is a meaningful broad definition of "power spectrum". It is understood that there are many numerical methods for calculating the frequency distribution of periodic signals and all of them are contemplated herein. The "spectrum" can be calculated for the range of natural respiratory frequencies which are generally between 0 and 1.0 Hz. In the disclosed embodiment, the frequency range of about 0.1 to 0.5 Hz was found. selected is referred to as the "respiratory rate band" (RFB) for the purposes of this disclosure. Other frequency ranges may be selected and the selection of this range is merely exemplary.

In Figure 3, the RFB 204 is indicated by the square frame that includes all relevant respiratory rates for the purposes of determining the timing efficiency in this example. The fact that the patient's natural respiration rate peaks at 0.4 Hz 202 can be expected from the respiration profile 101 in Figure 1. Another frequency band important for determining timing is called the "frequency band. stimulation frequency ”(SFB). It is represented by the narrow band square 203 and in this case it is centered on the frequency at which the trains of stimulation pulses are applied as in profile 103 of figure 2.

The spectral graph in Figure 3 corresponds to the period in which stimulation therapy is not applied. Power in the SFB band is low if the center frequency, in this case 0.3 Hz, is significantly different from the dominant respiratory rate 202.

The efficiency of respiratory synchronization can be determined by comparing the spectral power in the SFB band with the total spectral power or with the spectral power in other frequency bands, for example. The inventors have found it useful to designate a capture index (CI) as a measure of the efficacy of therapy. The capture index is calculated by dividing the spectral power in the SFB by the spectral power in the RFB. The capture index represents the fraction of the total breath spectral graph that is in the narrow band close to the pacing rate. It can be expected that the value of the capture index will increase proportionally with the timing of the pacing breath. Therefore, the pacing rate becomes the dominant frequency of the respiration signal as synchronization increases. There are many numerical calculations that can be used to calculate the catch rate. For example, the inventors used the following methodology, among others.

A spectral graph is a graphical technique for examining cyclic structure in the frequency domain. Strictly defined, it is a smoothed Fourier transform of the autocovariance function. Frequency is measured in cycles per unit of time. The spectral graph is represented by a vertical axis of smoothed variance (power) and a horizontal axis of frequency (cycles per observation).

The calculations can be used to generate the smoothed variances and are not discussed further in this document. Spectral graphs are a fundamental technique in time series frequency analysis and those of skill in the art are familiar with them. Spectral graphs can be used to determine how many cyclic components are in a cyclic waveform, whether or not there is a dominant cycle frequency, and if so, what is the dominant cycle frequency. For the purposes of this disclosure, the degree of "dominance" of the dominant frequency (pacing) refers to the capture rate.

In the example shown in Figure 3, the IC was calculated as: (power in the stimulation frequency range +/- 0.0183 Hz) / (power from 0.1 to 0.5 Hz). The width of the numerator in this example is 0.0366 Hz. It is calculated from the pacing rate value rounded to the nearest FFT “class” with the numerator width 3 classes below and 3 classes above ( 6 classes in total). The resolution in the frequency domain in this example is 0.0061 Hz / class. This is called the "class width." The choice of +/- 3 classes was made to account for something or the “class spread” that is observed when the pacing rate is not an exact FFT class rate and some natural variance in the rate of respiration. synchronized. The FFT intervals are set by the data sample rate (400 samples / s) and the FFT length (216 = 65,636).

The data sampling frequency was 400 samples / s. It is understood that other lower sample rates, eg 20 samples / second, may be more suitable for embedded software calculations or other applications. The record length was 65,536 samples (this corresponds to 164.84 seconds). If a lower data acquisition sample rate is used, significantly fewer samples are needed, but probably not less than, for example, 1,024 or 2,048. Other

ES 2 826 328 T3 record lengths, such as for example 2, 3 and 5 minutes. In this example the capture index is calculated as the ratio of the sum of the magnitudes of a frequency band 63 classes wide (0.0366 Hz), centered around the known stimulation frequency, and the sum of the magnitudes ( or power) from 0.1 to 0.5 Hz. Other window widths can be used for both SFB and RFB in different embodiments, and the SFB need not be centered on the pacing rate. In common to all embodiments, the "pacing frequency band" SFB is narrower than the "respiratory frequency band" (RFB), such as for example <10% of the RFB and is included within the RFB.

Figure 4 is a spectral graph of the respiration data presented in Figure 2. In this example, pacing is activated and applied at the preset frequency of 0.3 Hz as illustrated by profile 103 in Figure 2.

It can be seen that the peak of the respiratory signal power spectrum (air flow) 302 is at the frequency 0.3 Hz which corresponds exactly to the stimulation frequency. The natural breathing power at 0.4 Hz is reflected in a smaller peak 301. It is appreciated that the presence of the natural breathing frequency power in the spectrum can vary depending on the intensity of stimulation and the intrinsic respiratory impulse of the patient. . The presence of appreciable respiratory activity at the natural respiratory rate suggests that the respiratory drive is synchronized but still active, that is, it is not suppressed or latent. The power in the SFB 303 in this example represents a fraction of the RFB 304 greater than in the example illustrated by Figure 3. Therefore, it can be expected that the capture ratio (SFB / RFB) will also increase significantly. In fact, the calculation shows that the capture rate increased in this example from 0.24 (Figure 3) to 0.46 (Figure 4). Different calculation methods can result in different numbers, but the capture rate is significantly increased when the patient's breathing is synchronized.

Figure 5 is a graph of experimental data related to respiratory disorders in a patient treated according to embodiments of the invention. Figure 5 illustrates the practical importance of the capture rate in order to restore normal respiration in the periodic respiration environment. The severity of periodic breathing is usually characterized by the apnea-hypopnea index (AHI). AHI is the sum total of respiratory events (apneas and hypopneas) that occur in one hour. AHI> 15 is considered significant and AHI> 30 serious and very dangerous. Conventional clinical methods of calculating AHI during sleep studies using polysomnography (PSG) are known. PSG is a diagnostic test during which various physiological variables are measured and recorded during sleep. The graph of Figure 5 was obtained by the investigators using PSG in a patient suffering from severe periodic breathing while undergoing stimulation therapy according to embodiments of the invention. The patient's AHI is expressed on the Y-axis as a function of the capture index on the X-axis. During the experiment, the stimulation energy (in this case, the stimulation current) was varied generating different levels of diaphragmatic activation and, as a result, different levels of synchronization. The capture rate was subsequently calculated using a digitized record of the sleep study and a methodology equivalent to those described in this disclosure.

It can be seen that, during periods of time in which the capture index was higher, the AHI was reduced. Stimulation that resulted in capture rates greater than 0.5, as calculated in this example, virtually eliminated periodic respiration entirely.

It is understood that the use of FFT and the calculation of the respiratory spectrum are not the only way to implement the calculation of the capture rate. For example, the respiratory waveform can be processed and displayed as a series of numbers corresponding to respiration durations. A series representing the last 3-4 minutes of respiratory data may consist of, for example, 60-80 breath durations. A histogram of breath durations can be constructed representing the frequency distribution of breath durations. If intrinsic respiration is synchronized with a pacing rate, the rate of occurrence of breath durations corresponding to the wavelength of that rate will increase. For example, if the pacing rate is 20 / minute, the breath duration is 3 seconds. As capture and timing increase, breaths of approximately 3 seconds in length will occur with increasing frequency. To compensate for natural variability, breaths that are, for example, between 2.84 and 3.18 seconds in duration can be included in the numerator of the computed capture rate. This range of breath durations corresponds to the +/- 0.0183 Hz frequency band used in the spectrum-based example described above.

The capture index in this method is calculated as: (sum of occupations of breath durations in the pacing rate interval +/- selected band) / (sum of occupations of all breath durations in the respiratory interval). The respiratory range of breath durations can be, for example, from 2 to 10 s. The breath duration interval of 2 to 10 seconds corresponds to the respiratory rate of 0.1 to 0.5 Hz.

The histogram-based capture verification method is mathematically different from the spectrum-based method, but has a similar principle. It is based on the assumption that when pacing synchronizes respiration, the respiration durations of the respiratory signal in the immediate range of the pulse rate will occur significantly higher than those in other frequency bands.

ES 2 826 328 T3 respiratory. Therefore, the capture index is still calculated as the ratio of the variance of the breath signal found in the narrow band centered on the pacing rate to the total variance in the wider respiratory rate band. The inventors have shown in patients that the value of the capture index calculated using the histogram method increased proportionally to the synchronization of respiration by stimulation, thus allowing a therapy guided and closely correlated with the capture calculated using the spectrum method. It is appreciated that other capture rate calculation methods based on a similar principle are possible and will occur to those skilled in the art upon reading this disclosure.

Figure 6 is a waveform of respiration and pacing data associated with a patient therapy according to embodiments of the invention. The upper profile 501 represents a patient's breathing (air flow). The X-axis represents 16 minutes of data logging and individual breaths are compressed compared to Figures 1 and 2 which only showed one minute of data. During this therapy period, the stimulation energy (current) was first gradually reduced and then completely deactivated. The lower profile 503 represents the electrical stimulation current. During the first 3 minutes the current was kept constant at approximately 5 mA. Respiration 501 was sufficiently synchronized and no periodic respiration was present. During the 3 to 10 minute period of the recorded segment, current 503 was gradually reduced. It can be seen that periodic respiration is no longer controlled, and after 10 minutes the alternating apneas 504 and hyperpneas 503 return indicating the typical pattern of respiration periodic known as Cheyne-Stokes respiration.

Figure 7 is a control flow diagram according to embodiments of the present disclosure. Figure 7 illustrates a possible method and algorithm that takes advantage of the capture rate to implement and improve the therapy of breathing disorders. The proposed capture index methodology is understood to have broad implications for respiratory therapies using diaphragm or phrenic nerve stimulation and possibly mechanical ventilation.

An embodiment according to the present disclosure employs a capture rate type calculation incorporated into an algorithm in an implantable pulse generator (IPG) microprocessor that can adjust the phrenic nerve stimulation energy in response to the calculated capture rate. The capture rate can be calculated based on 2-3 minutes of history of a respiratory signal, eg, transthoracic impedance, and pacing parameters can be automatically adjusted based on the calculated capture rate.

The built-in algorithm of this embodiment can determine the intrinsic resting respiratory rate of patient 601. This rate may be, for example, between 6 and 40 breaths / minute, but in a targeted population of periodically breathing patients it is likely between 12 and 30 breaths / minute. The algorithm can apply trains of stimulation pulses to the patient's phrenic nerve at a set rate that in some embodiments is somewhat less than intrinsic rate 602. For example, it may be 2-4 breaths less than intrinsic rate.

Thus, if the algorithm determined that the patient was breathing at 20 breaths per minute, the pacing rate can be automatically set to 16 breaths per minute, for example. After sufficient respiratory signal information is collected by the embedded software (this may be, for example, 3 minutes of digitized data at 20 samples per second) a capture rate 603 can be calculated.

Since physiological conditions such as patient position, sleep state, diaphragm fatigue, and others can influence the response to timing, it can be expected that the capture rate will not be constant over time. There may be a preset target capture rate value that indicates the desired timing. This value can be in the range 0.2 to 0.8, for example. According to the known technique of feedback control engineering, a built-in algorithm can compare the actual capture rate with target 604 and increase the stimulation energy if the capture rate is below the target or decrease it if it is above the target. 605. The stimulation energy can be adjusted by varying the supplied current, voltage, frequency, or pulse duration. For example, the stimulation current can be increased or decreased in the range of 1 to 10 mA in suitable steps. Alternatively, the stimulation pulse duration can be increased or decreased in the range of 100 to 500 ps in suitable steps, for example. A feedback control algorithm can be implemented in IPG's embedded software, such as a PI or PID regulator known in the field of control engineering. In the embodiment used by the inventors to collect experimental data, the stimulation current was manipulated in steps of 0.1 to 0.5 mA to achieve the desired capture rate.

Figure 8 is a schematic view of a patient and therapy device according to embodiments of the present disclosure. An implantable pulse generator 702 is programmed to generate trains of stimulation pulses 703 at a fixed rate. A right phrenic nerve of patient 705 is enervated in the right hemidiaphragm 706. Stimulation pulse trains 703 are delivered to the right phrenic nerve 705 via electrode lead 704.

Either the phrenic nerve of the diaphragm itself can be stimulated. One or more electrodes may be placed on the diaphragm, adjacent to the nerve (eg, cuff electrode), intravenously proximal to the nerve, or at any other suitable location to provide appropriate stimulation. The electrode (s) can

ES 2 826 328 T3 connect to an electrical pulse generator using cables or wireless technology. The pulse generator can be implanted within the patient or placed externally.

The right phrenic nerve 705 conducts stimulation to the right hemidiaphragm 706, which responds with downward motion 707. Downward motion 707 of the diaphragm results in inflation of the lungs and activation of stretch receptors within the thoracic cavity. Periodic stretching is believed to generate a periodic regular rhythm of neuronal feedback inputs 708 to the brain 701. Respiratory neurons in the brain are synchronized by neuronal input 708. Stimulation intensity 703 elicits a proportional response from stimulated hemidiaphragm 706. Consequently, increased diaphragm movement results in increased regular periodic neuronal input 708 to the brain 701.

When the signals reach a necessary intensity, respiratory synchronization is present and the desired fixed and repetitive coupling is temporarily established between the stimulation, the mechanical inflation of the lungs and the inspiratory neuronal activity in the respiratory control center of the brain. Synchronization can occur at a ratio of 1: 1 (a mechanical inflation with respect to a neuronal respiratory effort), but other integral reasons, as well as occasional aperiodic, chaotic behavior, can be observed in the transition between different integral ratio synchronization patterns . The 2: 1 ratio of two paced inflates to neuronal respiratory effort is commonly seen in conjunction with the 1: 1 ratio.

The brain responds to synchronization with the regular periodic sequence of respiratory impulse 709 that is delivered to respiratory muscles of the diaphragm via both the right 705 and left 712 phrenic nerves as well as via the airway control nerves 710 to the muscles of the respiratory tract. respiratory resulting in the desired dilation of the airways 711. The left hemidiaphragm 715 is enervated by the left phrenic nerve 712 which is not stimulated by the IPG and therefore can sometimes show independent behavior in response to signals from the brain 701 and is not directly affected by the IPG 702 . The muscle groups of the right and left hemidiaphragms are known to be separately enervated by the right and left phrenic nerves and move independently in response to signals from these nerves. Synchronized respiratory activity of the unstimulated hemidiaphragm is an indication of synchronization as opposed to electrostimulation of respiration.

The IPG 702 can be equipped with additional leads 713 and means to measure respiration such as by transthoracic impedance sensing 714. Software embedded in the IPG programmable logic can respond to changes in respiration by adjusting the pacing pulse train rhythm 703. Respiratory detection 714 can also be used by IPG logic to set and change the rate of pacing pulse trains 703 depending on the intrinsic respiratory rate detected 709.

One skilled in the art will appreciate that the present disclosure can be practiced with embodiments other than those disclosed. The disclosed embodiments are presented for purposes of illustration and not limitation. The invention is defined solely by the following claims.