Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
  • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/103—Measuring devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
  • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb
  • A61B5/113—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb occurring during breathing
  • A61B5/1135—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor or mobility of a limb occurring during breathing by monitoring thoracic expansion
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
  • A61B5/316—Modalities, i.e. specific diagnostic methods
  • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
  • A61B5/346—Analysis of electrocardiograms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
  • A61B5/7271—Specific aspects of physiological measurement analysis
  • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N1/00—Electrotherapy; Circuits therefor
  • A61N1/18—Applying electric currents by contact electrodes
  • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
  • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
  • A61N1/362—Heart stimulators
  • A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
  • A61N1/36514—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure
  • A61N1/36521—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure the parameter being derived from measurement of an electrical impedance

Definitions

• the invention relates to a novel method for sensing respiratory and hemodynamic conditions and pacing the heart, utilizing a single catheter or several catheters, for treatment of heart-failure, low cardiac output or pulmonary congestion.
• the catheter enables measuring the instantaneous pleural pressure, based on measurements of the intravascular volume and pressure of an intrathoracic large elastic vessel.
• the invention may be used for treatment of cardiac decompensation, amelioration of dyspnea and prevention of deterioration to pulmonary congestion and pulmonary edema.
• the novel treatment is a breakthrough in the management of heart failure for the following main reasons: 1. It is based on a novel paradigm for understanding the deterioration of heart failure. 2. It counteracts the normal physiological control of cardiac pacing. 3. It is independent of the various etiologies of heart failure, and can treat all of them. 4. It provides assessment of the severity of cardiac decompensation and immediately provides a treatment that is proportional to the severity of the decompensation. 5. It can detect early deterioration and provide treatment before the patient may become symptomatic – provides personalized medicine with early detection and prevention. Advantages of the invention include, without limitation: 1. It applies to the huge market of heart failure, and can be used in all the patients with stage 3 and 4 heart failure. 2.
• Heart failure It applies to all forms of heart failure, independently of the etiology, whether it is heart failure with reduced ejection fraction or preserved ejection fraction. 3. It provides immediate treatment to the detected development of dyspnea or an increase in the intrapulmonary blood pressure (hemodynamic congestion). 4. It can detect the slow progression of the disease and treat it before the patients become symptomatic. Thus, it provides prevention and can decrease the rate of hospitalization. 5. It represents novel autonomic control (diagnosis and treatment) of the human autonomic cardiac system. It enables tight continuous surveillance of the heart-failure patients, with tight monitoring of the changes in the hemodynamic congestion and the effectiveness of the treatment. 6. It is simple to implement. It is based on integration of pacing technology with sensing the respiratory effort and a novel algorithm. 7.
• the present invention describes a novel intravascular catheter that can be used for both monitoring the respiratory and hemodynamic conditions and pacing the heart.
• the catheter is connected to a device that can modulate the cardiac rhythm and synchronize it to the respiratory phases and the pleural pressure.
• the catheter delivers the required inputs to the device and transmits the device pacing output to the heart. It enables to measure the instantaneous pleural pressure, based on measurements of the intravascular volume and pressure of an intrathoracic large elastic vessel.
• the catheter is used for treatment of heart failure, low cardiac output and pulmonary congestion and also for prevention of atrial fibrillation; without limitation, the invention may be used for treatment of cardiac decompensation, amelioration of dyspnea and prevention of deterioration to pulmonary congestion and pulmonary edema.
• the present invention includes methods and systems for sensing, diagnosing, and/or treating respiratory and hemodynamic conditions and for pacing the heart using a single catheter that includes one or more sensors and one or more pacing electrodes.
• the pacing electrodes may be at the tip of the catheter which is implanted in one of the heart chambers (atria or ventricle, right or left).
• the sensors along the catheter may be positioned within the venous circulation or the cardiac chamber.
• the sensors along the catheter may provide two type of information: sensing the cardiac and respiratory rhythm for real time control of the timing of the appropriate pacing, and sensing long-term hemodynamic and respiratory indices for assessing the severity of cardiac decompensation and respiratory effort.
• Sensing the cardiac rhythm and indices of cardiac decompensation may be done by sensing the cardiac autonomous electrical activity by the electrodes at the distal tip of the catheter, for (a) appropriate timing of pacing in cadence with cardiac autonomous pacing, and (b) monitoring the cardiac electrophysiological conditions by detecting arrhythmias and analyzing the changes in heart-rate variability as indices of the autonomic system activity and severity of cardiac decompensation. Assessing the severity of cardiac decompensation may be done by pressure transducer along the catheter, for sensing the severity of hemodynamic congestion and the increase in the central venous pressure or cardiac camber pressure.
• Sensing indices of cardiac decompensation may be done by measuring the changes in the vessel diameter or the changes in the volume in a segment of the vena-cava or within the cardiac chamber, as an index for the severity of blood congestion.
• the changes in the volume are monitored by measuring the changes in the electrical impedance.
• An increase in the vessel diameter decreases the impedance.
• the impedance is a hyperbolic function of the volume.
• the measurement of changes in the vascular impedance may be done with four electrodes along the catheter (and four wires), wherein the two distal electrodes are used for injecting alternate currents, and the two central electrodes are used for sensing the voltage.
• Sensing indices of cardiac decompensation may include the calculation of the respiratory-induced changes in the pleural pressure, an index of the respiratory effort and severity of cardiac decompensation, based on the measured intravascular pressure and the simultaneous changes in the intravascular blood volume. Sensing indices of cardiac decompensation may be done by measuring the changes in lung congestion by measuring the impedance between electrodes along the catheter, deep within the chest cavity and electrode on the pacemaker/controller. Monitoring the respiration may include monitoring the changes in the respiratory pattern as the changes in the ration between the inspiratory and expiratory intervals.
• Sensing signals include a combination of the following signals: a.
• the ECG is essential for the precise triggering of cardiac pacing, in the appropriate time after the last cardiac QRS signal. 4.
• the peak-to-peak amplitude of the pleural pressure is used as a surrogate to the respiratory effort. 5.
• the pleural pressure, intravascular volume, and intravascular pressure, pulmonary impedance and changes in the cardiac rhythm are used in combination or separately to define the respiratory phases and the severity of the respiratory effort.
• the pleural pressure (P PL ) is assessed from the measurements of the intravascular volume (V V ) and pressure (P V ), where C V is the vessel compliance, and it is constant.
• the vessel compliance (C V ) can be estimated noninvasively, by asking the patient to stop breathing at least two times, and to generate different mouth pressure each time.
• the thoracic impedance can be measured from the each of the catheter electrodes and the device (13 in the figures).
• the catheter can be implanted in each of the heart chambers (4, 5, 6, or 7).
• the preferred site is the right atrium (4) if the patient has normal sinus rhythm. If the patient has atrial fibrillation the preferred site is the right ventricle (5). 10.
• Several catheters can be used, some dedicated for the sensing and some dedicated for pacing.
• Sensing can be made simultaneously in the vena cava and some of the heart chamber (as the right atrium and right ventricle). Pacing can be done in both the atrium and the ventricle in case of atrioventricular block. It is noted that the term “catheter” encompasses any slender element suitable for mounting thereon or therein a pressure sensor and electrode. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be understood and appreciated more fully from the following detailed description taken in conjunction with the drawings in which: Fig. 1 is a simplified illustration of “respiratory sinus arrhythmia”, which is a normal physiological increase in the heart rate during inspiration and decrease in the heart rate during expiration (depicted by the arrows).
• the cardiopulmonary reverse cycling therapy of the invention counteracts with the normal physiology and increases the heart rate only when the intrathoracic pressure is close to zero, at end expiration and the beginning of inspiration.
• the proposed cardiopulmonary reverse cycling therapy causes a net decrease in hemodynamic and lung congestions, by increasing the absolute number of cardiac contractions during time intervals with close to zero intrathoracic pressure over time interval with deep negative intrathoracic pressure.
• Fig. 2 illustrates experimental validation, in sheep, of the effects of breathing on the right and left ventricle stroke-volumes. The changes in the pleural pressure have overt opposite effects on two ventricles.
• the decrease in the pleural pressure during inspiration is associated with an increase in the right-ventricle stroke-volume and simultaneous decrease in the left-ventricle stroke-volume.
• the maxima right ventricle output and the minimal left ventricle stroke volumes are reached at the deepest negative pleural pressure, at end-inspiration. Expiration yields the opposite, a decrease in the right-ventricle output and an increase in the left-ventricle output.
• pacing at mid and late expiratory phase promotes draining blood out of the lung through the left ventricle and decreases blood inflow into the lung through the right ventricle.
• FIG. 3 depicts an example of the inventive synchronization of the cardiac pacing to the changes in the intrathoracic pressure and swings in the respiratory wave, based on data from heart failure patient.
• the upper bars denote the imposed pacing (red bars) over the native regular sinus pacing (blue bars) on top of the recorded ECG.
• the lower trace presents the measured changes in the intrathoracic pressure.
• Note the patient suffers from severe dyspnea with respiratory effort (peak to peak amplitude) of 15 mmHg, about 5- fold the normal respiratory effort.
• the novel algorithm sets a threshold (at -5 mmHg in this example) and segments the respiratory cycles into two types of time intervals: (1) Time intervals with deep negative intrathoracic pressure (red), at end inspiration and early expiration.
• the catheter can be inserted into other chambers of the heart (5 – right ventricle, 6 – left atrium, 7 – left ventricle) and also several similar catheters can be used.
• the catheter is implanted in the right ventricle when the patient suffers from atrial fibrillation.
• Two catheters may be used, one in the right atrium and a second in the right ventricle when the patient suffers from atrioventricular conduction abnormalities.
• Figs. 5, 5A and 5B illustrate more detailed structure of the catheter (3).
• the catheter can deliver cardiac stimulation by the electrode of electrodes at distal end of the catheter (8, 9).
• the distal end (9) may include a sharp spring, which is inserted into the myocardium during the implantation, and stabilizes the position of the catheter.
• the novel therapy is called herein the “cardiopulmonary reverse cycle” or “breaking the vicious cardiopulmonary cycle” and it is doing it by changing the cardiac rhythm and slightly synchronizing the cardiac contractions to the different breathing phases.
• the normal physiological control of the heart rate aims to increase the cardiac output during exercises, and it is done efficiently in healthy subjects.
• An increase in the respiratory work by the “respiratory pump” (the diaphragm and all the respiratory and accessory muscles), decreases the intrathoracic pressure during inspiration and facilitates venous return to the right atrium.
• the cardiac output of the left ventricle is equal to the venous return, at steady state, and is limited by the venous return.
• the main strategy behind the present innovation is to utilize the “respiratory pump” and cardiac contractions in order to pump blood out of the lung and to alleviate the hemodynamic congestion. It is done by modulating cardiac pacing according to the changes in the pleural pressure, but counterintuitively, it is works opposite to the normal physiology and increases the heart rate during end expiration and early inspiration, as depicted in Figure 1 (Reversed Cardiopulmonary Cycling Therapy).
• the “respiratory pump” decreases the right- ventricle preload, decreases the left ventricle afterload and increases the left-ventricle preload
• the device increases the pacing rate to facilitate the removal of blood from the lung.
• the pressures in the pulmonary circulation (hemodynamic congestion) and the amount of blood and fluids with the lung (lung congestion) are mainly determined by the inflow of blood into the lung through the right ventricle and the outflow of blood out from the lung back into the peripheral circulation through the left ventricle.
• these inflow and outflow, through the right and left ventricle, are modulated by the intrathoracic pressure. In the presence of a deep negative intrathoracic pressure the inflow into the lung is larger than the outflow from the lung.
• the device utilizes the works that are generated by the respiratory system (the “respiratory pump”) and cardiac contractions in order to remove fluids from the lung. It utilizes the effects of the pleural pressure generated by the “respiratory pump”, to “pump” out of the lung and to reduce the workloads on the left ventricle. It is done by pacing the heart and increasing the number of heart beats when the intrathoracic pressure is close to zero relative to the number during deep negative intrathoracic pressure.
• the cardiac workload decreases the (1) LV afterload, when the LV contract from higher surrounding pressure, (2) LV preload, by gradual decreasing lung congestion and the pulmonary venous pressure, and (3) RV afterload, by decreasing pulmonary congestion and pulmonary vascular resistance.
• the mean cardiac stroke volume of an adult is about 70 ml.
• Our preclinical studies in sheep revealed huge effects of the pleural pressure on the stroke-volumes of the two ventricles, as depicted in Figure 2.
• the LV output decreases by about 10% at end- inspiration and increases by 10% above the mean at mid-expiration (Fig. 2). Based on our recent preclinical data, pacing when the pleural pressure is high provide a net shift of 0.5 ml of blood out of the lung in each breath cycle.
• Pacing during the inspiratory phase as suggested by other patents US 8509902, US 8483833) may only accentuates the vicious cycle and lung congestion, since pacing at low negative intrathoracic pressure increases the right-ventricle output, but increases the failing left-ventricle afterload and decreases the left-ventricle filling. This this mode can ultimately lead to progressive lung congestion and cardiac decompensation.
• No prior art relates to intravascular catheter that is used for simultaneous monitoring of respiratory and hemodynamic indices and pacing the heat. The utilization of a single catheter simplifies the implantation procedure and significantly reduces the immediate and long-term complications.
• the present invention provides treatment with precise synchronization of cardiac pacing to the respiratory dynamic, with a significantly better resolution of less than 30 milliseconds.
• the present invention uses a different technique than the prior art, the technique being based on simultaneous measurement of both the intravascular pressure and the intravascular volume. The instantaneous pleural pressure is calculated from these two measurements, after the elastic vessel compliance was calibrated.
• the synchronization of cardiac pacing to the respiratory dynamics is not aligned to a simple segmentation of breathing cycle to inspiration and expiration phase, but rather uses more precise assessment of the pleural pressure dynamics and defines a threshold that relates to the pleural pressure level, as depicted in Fig. 3.
• Inspiration is defined as the time interval of inhalation, when the intrathoracic pressure drops from a pressure close to zero to the lowest negative intrathoracic pressure.
• pacing during the early expiratory phase is ineffective, since the intrathoracic pressure is very low at the beginning of the expiration phase.
• the appropriate pacing widow crosses the inspiration and expiration phases, and starts before the end expiration and ends after the beginning of inspiration. This segmentation of the respiratory cycle is unique to this embodiment, in comparison the all the other suggested pacing of the heart (such as US 8509902, US 8483833).
• the catheter includes a combination of sensors that assist in the diagnosis and quantification of heart failure severity and define when to pace the heart within the respiratory cycle. This includes: .
• the intracardiac ECG and the respiratory induced changes in the intracardiac electrocardiography (8 and 9 in Fig. 5).
• the ECG is essential for the precise triggering of cardiac pacing, in the appropriate time after the last cardiac QRS signal.
• Intravascular pressure measurements within any of the intrathoracic arterial or venous vessels (12 in Fig. 5), since the pressures within the intrathoracic vessels increases with cardiac decompensation, and the intravascular pressure is modulated by the changes in the intrathoracic/pleural pressure.
• the heart and the great vessels are within the mediastinum and are surrounded by the intrathoracic pressure.
• breathing changes all the intrathoracic, intravascular, and intracardiac pressures.
• the respiratory effort also affects the mean intravascular pressure.
• An increase in the respiratory effort is associated with an increase in the mean intravascular pressure, since it increases the pulmonary vascular resistance.
• Intravascular volume measurement within any of the intrathoracic arterial or venous vessels, utilizing the impedance technology (10, 11 in Fig. 5). Cardiac decompensation is associated with an increase in the intravascular pressure and volume. However, there is no simple linear relationship between the two, but an exponential one. At low intravascular pressure, the vessel compliance is large, and significant changes in the volume are associated with smaller changes in the intravascular pressure.
• the intravascular volume is more sensitive to the severity of congestion.
• Assessment of pulmonary congestion by the impedance technology between any electrodes along the catheter and the device (13 in Fig. 5). Measurement of the intrathoracic (pleural) pressure.
• the peak-to-peak amplitude of the pleural pressure is used as a surrogate to the respiratory effort.
• the pleural pressure defines when to pace the heart, based on the instantaneous absolute value of the pleural pressure (and not just the peak-to-peak amplitude).
• the pleural pressure (PPL) is assessed from the measurements of the intravascular volume (VV) and pressure (PV): where CV is the vessel compliance, and it is constant.
• more calibration data points will improve the precision of the calibration and will enable to consider nonlinear compliance (a decrease in the vessel compliance at large intravascular volumes).
• Measurement of the pleural pressure is based on the fact that the compliances of the central blood vessels (as the vena-cava, pulmonary artery and aorta) are determined by the passive elastic properties and are practically constants within a period of several months.
• C V is the vessel compliance
• V V (t) is the vessel blood volume
• P V (t) is the intravascular pressure
• P PL (t) is the pleural pressure.
• Knowing the intravascular volume (V v (t)) and pressure (P V (t)) enable to calculate the pleural pressure:
• the vessel compliance can be assessed noninvasively, by asking the patient to stop breathing at least at two pressures. When there is no air-flow, the alveolar pressure (PA ⁇ ) is equal to the pressure measured at the mouth (PM).
• Equation 4 includes two constants: C V and C LW .
• V V1 ,V V2 intravascular volume
• P V1 ,P V2 intravascular pressure
• P M1 ,P M2 the pressure at the mount
• the catheter can be implanted in each of the heart chambers (4, 5, 6, or 7 in Fig. 4).
• the preferred site is the right atrium (4) if the patient has normal sinus rhythm. If the patient has atrial fibrillation the preferred site is the right ventricle (5 in Fig 4).
• Several catheters can be used. Some can provide the sensing and others the pacing. Sensing can be made simultaneously in the vena cava and within the heart chamber (as the right atrium and right ventricle). Pacing can be done in both the atrium and the ventricle in case of atrioventricular block.
• the intravascular volume, and intravascular pressure, pulmonary impedance and changes in the cardiac rhythm can be used in combination or separately for the analysis of cardiac decompensation severity.
• the pleural pressure, intravascular volume, intravascular pressure, pulmonary impedance and changes in the cardiac rhythm can be used in combination or separately to define the inspiration and expiration phases, and may assist in determining the pacing time period within the respiratory cycle.
• Applications of the invention include, without limitation, treatment of heart failure patients including all heart failure types, treatment of low cardiac output and lung congestion.
• the invention is useful for: • Early diagnosis of decompensation, for prevention of deterioration. It can monitor the early signs of deterioration, as increase in intravascular volume, increase in the respiratory effort (pleural pressure). • Adaptive (real time) modulation of cardiac pacing based on the assessment of the respiratory effort severity and cardiac decompensation severity.

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