Methods and systems for applying blood pressure lowering stimulation therapy to a patient

Abstract

Provided are a method and a system for applying and optimizing a patient's blood pressure lowering stimulation therapy. 【Solution means】It includes establishing the patient's baseline blood pressure parameters, applying a predefined stimulation pattern, and determining whether the predefined stimulation pattern meets the specified acceptance criteria. If the predefined stimulation pattern does not meet the specified acceptance criteria, a new stimulation pattern is calculated and applied, and it is determined whether the new stimulation pattern meets the specified acceptance criteria. From among the applied predefined stimulation pattern and the applied new stimulation pattern, the most suitable stimulation pattern for the patient is determined, and the most suitable stimulation pattern for the patient is applied.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 365,299, filed May 25, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to the field of treating hypertension, and more particularly to methods and systems for applying (also referred to herein as "customizing") a blood pressure lowering stimulation therapy to the physiological functions of a particular patient.

Background Art

[0003] Methods and systems for cardiac stimulation have been developed to lower a patient's blood pressure. There remains a need to customize such stimulation therapies according to the needs of a particular patient.

Summary of the Invention

[0004] This specification discloses methods and systems for customizing and optimizing a blood pressure lowering stimulation therapy.

[0005] One aspect of the present invention is a system and method for setting a stimulation pattern for continuously lowering a patient's blood pressure by reducing fullness and regulating baroreflex in response to a pressure drop, as described in U.S. Patent No. 10,967,188, issued April 6, 2021, the entire disclosure of which is incorporated herein by reference. In this context, the therapy can be customized and optimized. In particular, in an embodiment, by implementing a setup process that provides specific customized and optimized stimulation parameters based on the various physiological functions of various patients, the blood pressure lowering stimulation as a therapy for hypertension is improved. The embodiment provides a method and system for selecting an optimal set of stimulation parameters specific to a particular physiological function of a patient.

[0006] As one embodiment, a method for customizing a blood pressure lowering stimulation therapy for a patient may be provided. The method includes determining a patient's baseline blood pressure parameter, applying a predetermined stimulation pattern, and determining whether the predetermined stimulation pattern meets a specified acceptance criteria, calculating and applying a new stimulation pattern if the predetermined stimulation pattern does not meet the specified acceptance criteria, and determining whether the new stimulation pattern meets the specified acceptance criteria, determining an optimal stimulation pattern for the patient from among the applied predetermined stimulation pattern and the applied new stimulation pattern, and applying the optimal stimulation pattern to the patient.

[0007] In one aspect of the present invention, meeting the specified acceptance criteria may include calculating one or more parameters including an average systolic measurement value, a slope, an individual error, and / or an average error when determining whether any predetermined stimulation pattern meets the specified acceptance criteria and when determining whether any new stimulation pattern meets the specified acceptance criteria, and comparing each calculated parameter among the one or more calculated parameters with an allowable range of values of each calculated parameter.

[0008] In another aspect, meeting the specified criteria may further include calculating a weighted score for a stimulus pattern by multiplying each of one or more parameters (such as mean systolic measurements, slope, individual errors, and / or mean error) by a weighting factor of a predetermined parameter when determining whether an arbitrary predetermined stimulus pattern meets the specified criteria and when determining whether an arbitrary new stimulus pattern meets the specified criteria, and then comparing the calculated weighted score of the stimulus pattern with the weighted scores of other stimulus patterns and / or a predetermined required minimum weighted score. The weighting factors of the predetermined parameters may reflect the relative importance of the characteristics of the therapies for different patients. In one embodiment, for a patient known to have high blood pressure variability, a lower parameter weight score may be assigned to an individual error or a mean error. In another embodiment, a lower parameter weight score may be assigned to the mean systolic measurement of a relatively mild hypertensive patient compared to another more severe hypertensive patient who may be assigned a higher parameter weight score for mean systolic measurement.

[0009] In another aspect of the invention, the slope, individual errors, and mean error may be calculated by linear approximation.

[0010] In another aspect, the mean systolic measurement may be calculated using only a short AV delay subset of systolic blood pressure values.

[0011] In another aspect, the baseline blood pressure parameter may include at least one of the mean systolic measurement, approximate slope, individual error, or mean error.

[0012] In another aspect, determining the patient's baseline blood pressure parameter may include measuring the pre-stimulus baseline blood pressure before applying the first stimulation pattern and during a non-activated period, applying the first stimulation pattern, measuring the baseline blood pressure after the first stimulation after applying the first stimulation pattern and during a non-activated period, and determining the patient's first baseline blood pressure based on the measured pre-stimulus baseline blood pressure and the measured baseline blood pressure after the first stimulation. The first baseline blood pressure may be used to determine the effect of the first stimulation pattern on the first blood pressure, and the effect on the first blood pressure may be used to determine whether the first stimulation pattern meets the specified criteria.

[0013] In another aspect, determining the patient's first baseline blood pressure may include calculating the average of the measured pre-stimulus baseline blood pressure and the measured baseline blood pressure after the first stimulation.

[0014] In another aspect, determining the patient's baseline blood pressure parameter may further include applying a second stimulation pattern, measuring the baseline blood pressure after the second stimulation after applying the second stimulation pattern and during a non-activated period, and determining the patient's second baseline blood pressure based on the measured baseline blood pressure after the first stimulation and the measured baseline blood pressure after the second stimulation. The second baseline blood pressure may be used to determine the effect of the second stimulation pattern on the second blood pressure, and the effect on the second blood pressure may be used to determine whether the second stimulation pattern meets the specified criteria.

[0015] In another aspect, each of the predetermined stimulation patterns may include a periodic stimulation pattern consisting of a plurality of beats with a shorter atrioventricular delay followed by a plurality of beats with a longer atrioventricular delay. Calculating a new stimulation pattern includes identifying the stimulation pattern that provides the best effect among the predetermined stimulation patterns previously applied, determining whether the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, and if the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, reducing the shorter atrioventricular delay of the predetermined stimulation pattern that provides the best effect by an increment and determining whether a stimulation pattern with the reduced shorter atrioventricular delay has been applied. If a stimulation pattern with the reduced shorter atrioventricular delay has not been applied, designating the stimulation pattern with the reduced shorter atrioventricular delay as the new stimulation pattern to be applied to the patient. If a stimulation pattern with the reduced shorter atrioventricular delay has been applied, reducing the number of beats with the shorter atrioventricular delay of the stimulation pattern with the reduced shorter atrioventricular delay to provide a stimulation pattern with the reduced shorter atrioventricular delay and fewer beats, and designating the stimulation pattern with the reduced shorter atrioventricular delay and fewer beats as the new stimulation pattern to be applied to the patient.

[0016] In another aspect, a method for customizing a blood pressure lowering stimulation therapy for a patient, if a predetermined stimulation pattern that provides the best effect does not have an acceptable level of stability, increases the longer atrioventricular delay of the predetermined stimulation pattern that provides the best effect by an increment and determines whether a stimulation pattern with the increased longer atrioventricular delay has been applied, and if a stimulation pattern with the increased longer atrioventricular delay has not been applied, designates a stimulation pattern with the increased longer atrioventricular delay as a new stimulation pattern to be applied to the patient, and if a stimulation pattern with the increased longer atrioventricular delay has been applied, decreases the shorter atrioventricular delay of the stimulation pattern with the increased longer atrioventricular delay by an increment to provide a decreased shorter atrioventricular delay stimulation pattern and designates the decreased shorter atrioventricular delay stimulation pattern as a new stimulation pattern to be applied to the patient.

[0017] In another aspect, a method for customizing a blood pressure lowering stimulation therapy for a patient may further include limiting the application of a predetermined stimulation pattern and the application of a new stimulation pattern within a time allocated based on the patient's needs.

[0018] In another aspect, a method for customizing a blood pressure lowering stimulation therapy for a patient may further include determining an examination protocol based on the patient's baseline blood pressure parameters.

[0019] In another aspect, the examination protocol may include at least one of the total time to complete the method, a specific predetermined stimulation pattern for the patient, the number and / or time of the predetermined stimulation pattern applied to the patient, or the number and / or time of the new stimulation pattern applied to the patient.

[0020] In another aspect, the designated criteria may include at least one of slope and error.

[0021] In another aspect, the specified determination criterion may include at least one of a blood pressure stop condition, a lower limit of blood pressure drop, or a noise limit of measurement results.

[0022] In another aspect, calculating and applying a new stimulation pattern may include obtaining systolic blood pressure values and diastolic blood pressure values before stimulation (typically 0 to 300 seconds before stimulation), during stimulation, and after stimulation (typically 0 to 300 seconds after stimulation).

[0023] In another aspect, calculating and applying a new stimulation pattern may include calculating parameters within and between cycles.

[0024] In another aspect, the method may further include repeating the method to account for changes in the patient's physiological functions, changes in drug regimens, different times of day, different activity levels of the patient, and / or different heart rates of the patient.

[0025] Another embodiment may provide a system for customizing a blood pressure lowering stimulation therapy for a patient. The system may include at least one controller, a stimulation device configured to generate a control signal related to the patient's heart, and a control circuit configured to send the control signal to the patient's heart. The at least one controller may be configured to apply a predetermined stimulation pattern to determine whether the specified determination criterion is met by the predetermined stimulation pattern, and if the specified determination criterion is not met by the predetermined stimulation pattern, calculate and apply a new stimulation pattern to determine whether the specified determination criterion is met by the new stimulation pattern.

[0026] In one aspect, the at least one controller may be external to the stimulation device.

[0027] In another aspect, the system may further include a blood pressure measurement device configured to provide blood pressure data to the at least one controller.

[0028] In another aspect, at least one controller may be configured to calculate one or more parameters including mean systolic measurements, slopes, individual errors, and / or mean errors when determining whether any predetermined stimulation pattern meets a specified criterion and when determining whether any new stimulation pattern meets the specified criterion, and to compare each calculated parameter among the one or more calculated parameters with an acceptable range of values of each calculated parameter.

[0029] In another aspect, at least one controller may be configured to calculate a weighted score of a stimulation pattern by multiplying each of one or more parameters by a weight coefficient of a predetermined parameter when determining whether any predetermined stimulation pattern meets a specified criterion and when determining whether any new stimulation pattern meets the specified criterion, and to compare the calculated weighted score of the stimulation pattern with the weighted scores of other stimulation patterns and / or a predetermined required minimum weighted score.

[0030] In another aspect, the slope, individual errors, and mean errors may be calculated by linear approximation.

[0031] In another aspect, the mean systolic measurement may be calculated using only a short atrioventricular delay subset of systolic blood pressure values.

[0032] In another aspect, at least one controller may be configured to determine a patient's baseline blood pressure parameter, determine an optimal stimulation pattern for the patient from among the applied predetermined stimulation pattern and the applied new stimulation pattern, and apply the optimal stimulation pattern for the patient.

[0033] In another aspect, the baseline blood pressure parameter may include at least one of a mean systolic measurement, an approximate slope, an individual error, or a mean error.

[0034] In another aspect, at least one controller is configured to determine a patient's baseline blood pressure parameter by measuring a pre-stimulus baseline blood pressure during a period before applying a first stimulation pattern and while not activated, applying the first stimulation pattern, measuring a post-first-stimulation baseline blood pressure during a period after applying the first stimulation pattern and while not activated, and determining the patient's first baseline blood pressure based on the measured pre-stimulus baseline blood pressure and the measured post-first-stimulation baseline blood pressure. The first baseline blood pressure may be used to determine the effect of the first stimulation pattern on the first blood pressure, and the effect on the first blood pressure may be used to determine whether the first stimulation pattern meets a specified criterion.

[0035] In another aspect, determining the patient's first baseline blood pressure may include calculating an average of the measured pre-stimulus baseline blood pressure and the measured post-first-stimulation baseline blood pressure.

[0036] In another aspect, at least one controller is further configured to determine a patient's baseline blood pressure parameter by applying a second stimulation pattern, measuring a post-second-stimulation baseline blood pressure during a period after applying the second stimulation pattern and while not activated, and determining the patient's second baseline blood pressure based on the measured post-first-stimulation baseline blood pressure and the measured post-second-stimulation baseline blood pressure. The second baseline blood pressure may be used to determine the effect of the second stimulation pattern on the second blood pressure, and the effect on the second blood pressure may be used to determine whether the second stimulation pattern meets a specified criterion.

[0037] In another aspect, each of the predetermined stimulation patterns may include a periodic stimulation pattern consisting of a plurality of beats with a shorter atrioventricular delay followed by a plurality of beats with a longer atrioventricular delay. At least one controller is configured to identify the stimulation pattern that provides the best effect among the previously applied predetermined stimulation patterns, determine whether the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, and if the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, decrease the shorter atrioventricular delay of the predetermined stimulation pattern that provides the best effect by an increment and determine whether a stimulation pattern with the decreased shorter atrioventricular delay has been applied. If a stimulation pattern with the decreased shorter atrioventricular delay has not been applied, designate a stimulation pattern with the decreased shorter atrioventricular delay as a new stimulation pattern to be applied to the patient. If a stimulation pattern with the decreased shorter atrioventricular delay has been applied, reduce the number of beats with the shorter atrioventricular delay of the stimulation pattern with the decreased shorter atrioventricular delay, provide a stimulation pattern with the decreased shorter atrioventricular delay with the beats reduced, and designate the stimulation pattern with the decreased shorter atrioventricular delay with the beats reduced as a new stimulation pattern to be applied to the patient, so as to calculate a new stimulation pattern.

[0038] In another aspect, if the predetermined stimulation pattern that provides the best effect does not have an acceptable level of stability, at least one controller is further configured to increase, by an increment, the longer atrioventricular delay of the predetermined stimulation pattern that provides the best effect, and determine whether a stimulation pattern having the increased longer atrioventricular delay has been applied; if a stimulation pattern having the increased longer atrioventricular delay has not been applied, designate, as a new stimulation pattern to be applied to the patient, a stimulation pattern having the increased longer atrioventricular delay; and if a stimulation pattern having the increased longer atrioventricular delay has been applied, decrease, by an increment, the shorter atrioventricular delay of the stimulation pattern having the increased longer atrioventricular delay to provide a decreased shorter atrioventricular delay stimulation pattern, and designate, as a new stimulation pattern to be applied to the patient, the decreased shorter atrioventricular delay stimulation pattern, so as to calculate a new stimulation pattern.

[0039] In another aspect, at least one controller may be configured to limit the application of a predetermined stimulation pattern and the application of a new stimulation pattern within a time assigned based on the patient's needs.

[0040] In another aspect, at least one controller may be configured to determine an inspection protocol based on the patient's baseline blood pressure parameters.

[0041] In another aspect, the inspection protocol may include at least one of the total time for completing the customization of the patient's blood pressure lowering stimulation therapy, a specific predetermined stimulation pattern for the patient, the number and / or time of the predetermined stimulation pattern applied to the patient, or the number and / or time of the new stimulation pattern applied to the patient.

[0042] In another aspect, the specified criteria may include at least one of slope and error.

[0043] In another aspect, the specified determination criteria may include at least one of a blood pressure stop condition, a lower blood pressure limit, or a noise limit of the measurement result.

[0044] In another aspect, at least one controller may be configured to calculate a new stimulation pattern by obtaining systolic blood pressure values and diastolic blood pressure values 0 to 300 seconds before stimulation, during stimulation, and 0 to 300 seconds after stimulation.

[0045] In another aspect, at least one controller may be configured to calculate a new stimulation pattern by calculating parameters within and between periods.

[0046] Other systems, methods, features, and advantages of the present invention will be apparent to or will become apparent to those of ordinary skill in the art upon examination of the following drawings and detailed description. Such additional systems, methods, features, and advantages are all included within this description and this summary, are within the scope of the present invention, and are intended to be protected by the following claims.

[0047] The present invention can be better understood by reference to the following drawings and description. The components in the figures are not necessarily drawn to scale and emphasis is placed on illustrating the principles of the present invention. Further, in the figures, like reference numerals indicate corresponding parts throughout the different figures.

Brief Description of the Drawings

[0048]

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[0049] Embodiments of the present invention provide methods and systems for applying and optimizing blood pressure lowering stimulation therapy. These methods and systems may set stimulation parameters that result in a desired range of blood pressure lowering maintained over a long period.

[0050] Embodiments of this method and system enable the adjustment of stimulation pattern parameters based on multiple sequences of blood pressure measurements. The sequences include multiple measurements taken before the activation of therapy and, subsequently, a sequence of blood pressure measurements taken after the activation of therapy using a defined set of parameters. By this method, a pressure drop and a slope of the pressure change, which may be positive, negative, or close to zero, are determined. Based on the absolute change in blood pressure and the slope of the measured change over time, the effect on blood pressure is assigned a score that can be used to determine the best set of parameters to achieve the optimal long-term effect on blood pressure for a particular patient's physiology.

[0051] Embodiments of the method and system may take into account not only other factors that affect blood pressure measurements, such as respiration, ectopic beats, the patient's mental state, distractibility, etc., but also the natural variability between consecutive blood pressure measurements. The method and system may determine a measure of variability and determine whether the measurements have achieved a specified minimum consistency that permits their use. If the consistency criteria are not met, embodiments may take additional measurements to ensure consistency.

[0052] Hypertension is defined as having a systolic (maximal high) blood pressure above a specific (normal) threshold, a diastolic (minimal low) blood pressure above a specific (normal) threshold, or both. Methods of treating hypertension are typically measured by a drop in systolic blood pressure (SBP). Thus, while this specification focuses on the drop in SBP, the same method can also be applied to a drop in diastolic blood pressure (DBP).

[0053] In one embodiment, a method and system for customizing and optimizing blood pressure lowering stimulation therapy may include determining a patient's baseline blood pressure parameters (e.g., mean SBP, slope, error, and mean error), applying a predetermined stimulation pattern, and determining whether any predetermined stimulation pattern meets a specified criterion. If the predetermined pattern does not meet the criterion, calculating and applying new stimulation pattern parameters, and determining whether any new stimulation pattern meets the specified criterion. Determining an optimal stimulation pattern (predetermined or new) for a particular patient, and applying the optimal stimulation pattern for a particular patient. This iterative approach may enable therapy optimization by determining the patient's blood pressure levels (systolic and diastolic) under various possible therapies (e.g., from both predetermined and calculated stimulation patterns) and selecting the therapy that achieves the optimal result for the patient.

[0054] FIG. 1 shows a method 100 for customizing and optimizing blood pressure lowering stimulation therapy according to one embodiment. As shown, method 100 begins in step 102 by determining a patient's initial baseline blood pressure parameters and an appropriate test protocol for the patient.

[0055] As shown in FIG. 2, this step 102 of determining parameters may include preparing the patient for stimulation application and blood pressure measurement in step 202, measuring the initial baseline blood pressure and calculating parameters in step 204, and determining an appropriate test protocol for the patient in step 206. Determining the protocol may include determining the total time of the customization method assigned to the patient, a particular predetermined stimulation pattern for the patient, the number and / or time of the predetermined patterns applied to the patient, and / or the number and / or time of the calculated patterns applied to the patient.

[0056] In the embodiment, for blood pressure measurement, in a doctor's consulting room, a measuring device capable of providing a highly reliable index of the patient's systolic blood pressure and optionally diastolic blood pressure under resting conditions may be used. A highly reliable index means, for example, that the measurement may have a known bias from the actual systolic blood pressure. Such highly reliable measurements should preferably be obtained from the device at intervals within 120 seconds to provide sufficient information. The device may be an implantable, manual or automatic cuff-type blood pressure measuring device, or any other device that provides appropriate blood pressure measurement.

[0057] In determining the patient's initial baseline blood pressure parameters and test protocol in step 102, the embodiment may determine, for example, the total time for applying various therapies suitable for the patient's needs (such as in step 206) based on the patient's initial baseline blood pressure parameters. In the embodiment, the total time may range from about 15 minutes to about 60 minutes depending on the patient's needs. In the embodiment, the blood pressure level (systolic and diastolic) of the patient may be measured over a time period of about 3 minutes or more and about 10 minutes or less, either at the baseline level or when a specific therapy is applied. The 10-minute upper limit of this range may allow several separate blood pressure measurements to be obtained even using a slower measuring device. The 3-minute lower limit of the range may be useful even when using a much faster device to determine the slope (if any) of the change in blood pressure over time while averaging various factors affecting blood pressure, such as respiration, transient arrhythmias (such as ventricular premature contractions), and the patient's cough. There are various methods for obtaining highly reliable measurements at shorter time intervals. These methods include, but are not limited to, (1) non-invasive continuous blood pressure measurement using an infrared transmission plethysmograph (such as Finapres NOVA (registered trademark)) with a finger cuff, and (2) devices based on pulse transit time (PTT) or photoplethysmography (PPG) (such as Apple Watch, Galaxy Watch).

[0058] In step 102 and the next step of evaluating possible therapies, the measured systolic blood pressure values, together with the times at which they were measured, may be used to calculate one or more of the following parameters: · Mean systolic blood pressure (SBP): The mathematical mean systolic value of the measurements. · Slope: The slope of the approximation (preferably linear least squares) of the measurements, taking into account both the measurement time and the measured values. · Error (or individual error): The calculation error of the individual measured systolic values (on the time-value graph) from the linear approximation used to calculate the slope. · Mean error: The mean of the calculated individual errors above, preferably the mathematical mean.

[0059] In an embodiment, when determining systolic blood pressure at baseline or as a response to a particular therapy, if the measurements obtained are sufficiently accurate, the number of measurements (and thus the time spent on measurements) may be reduced. Once sufficient separate measurements of systolic blood pressure have been obtained (e.g., at least 3 times), sufficient accuracy may be calculated by calculating the individual errors and mean error of the measurements. Sufficient accuracy may be determined in various ways, such as comparing the mean error to a predetermined threshold, comparing the rate of change of the mean error to a predetermined threshold (using additional measurements), and / or comparing the median error to a predetermined threshold. By allowing the end of blood pressure measurement before the maximum allowable time has elapsed, the process of setting up the therapy may be speeded up, or more calculation steps may be enabled using the same setup time, thereby possibly enabling the identification of a more appropriate stimulation pattern for the patient.

[0060] Once the patient's initial baseline blood pressure parameters and the test protocol are determined, method 100 continues in step 104 by applying one or more predetermined stimulation patterns to determine the resulting blood pressure changes and effects. In an embodiment, measurements may be made using at least two predetermined sets of stimulation parameters. The predetermined sets of stimulation parameters may be based on past parameters that produced a desired effect in a past patient population. These first predetermined sets can be adjusted based on the patient's specific physiological state, such as systolic blood pressure, average heart rate, diastolic blood pressure, and changes in blood pressure throughout the day. Based on the measured effects (e.g., absolute change, slope, and error), an embodiment may calculate additional sets of parameters that are more likely to produce an optimal effect based on a predetermined set of rules.

[0061] If the total time allotted to method 100 is kept constant, there may be a trade-off between the number of predetermined stimulation patterns used as part of method 100 and the number of newly calculated stimulation patterns (described in detail below).

[0062] By using more predetermined stimulation patterns, it may be possible to achieve a sufficient blood pressure reduction in one of them by changing the stimulation pattern parameters, applying those patterns to the patient, and without the need for effect measurements. This may be useful, for example, for patients who require only a smaller blood pressure reduction that is easier to achieve. The use of a smaller number of predetermined stimulations leaves more time for newly calculated stimulations and may be useful, for example, for patients who require a larger blood pressure reduction. Optimally, in almost all patients, time should be left for one or two iterations regarding changes in stimulation parameters.

[0063] In an embodiment, the total time assigned to method 100 may be fixed (or preset), or may be set by the user. The total time may also depend on the patient. For example, patients who require a greater blood pressure reduction may be assigned a longer treatment time to enable better optimization of the therapy.

[0064] Referring again to FIG. 1, this method 100 may continue in step 106 by determining whether a predefined stimulation pattern meets the specified criteria for a particular patient. The criteria may be specified by user input and may be used by method 100 to determine whether a therapy suitable for a particular patient has been achieved. Based on that determination, in step 106, method 100 either accepts a predefined stimulation pattern that meets the criteria or, if the predefined stimulation pattern does not meet the criteria, continues to search for a better therapy for the particular patient (proceeding to step 112, described below).

[0065] In an embodiment, at least one of the criteria may be a stop condition for method 100, preferably indicating a sufficient blood pressure reduction. In an embodiment, this criterion (typically expressed as a drop in mmHg of blood pressure) can be the desired blood pressure change from the baseline. Alternatively, this criterion can be the absolute value of the systolic pressure desired for the patient, or this criterion can be the percentage of the drop from the baseline pressure. This criterion, like the other criteria, can be predefined for all patients or patient groups (based on characteristics), or can be set manually by the physician for each patient.

[0066] In another embodiment, the other criterion can include, for example, a blood pressure drop lower limit to avoid a blood pressure drop that is too large for a particular patient. Method 100 can be configured such that, even if a sufficiently large blood pressure drop is achieved, or even if it is considered too large for the patient, it does not stop so that a smaller decrease can be sought that is still sufficiently large to be therapeutically effective. For example, a patient with a baseline systolic blood pressure of 135 can be given a stop condition of a desired blood pressure drop of 10 mmHg, but if the therapy parameter set results in a pressure drop to 100 mmHg (a 35 mmHg drop) that is not therapeutically beneficial, Method 100 can be given a stop condition of a "too large" drop value of 25 mmHg so that it does not stop even though this drop is larger than the stop condition because it is larger than the "too large" drop value.

[0067] In another embodiment, as another example, the criterion can be based on the "noise" of the measurement results. A "too noisy" result may, for example, have too large an error even though the blood pressure drop is satisfactory. For example, there are various ways to determine that the error value is "too large", such as the average calculation error being larger than a predetermined value, the average calculation error being a specified percentage (e.g., about 25%) larger than the largest other error value obtained in any of the other measurements performed by Method 100, and / or the average calculation error being a specified percentage (e.g., about 100%) larger than the average error value obtained in any of the other measurements performed by Method 100.

[0068] Thus, as shown in FIG. 1, the embodiment includes 1. determining an initial baseline blood pressure parameter (e.g., mean SBP, slope, error, and mean error) and an examination protocol (step 102); 2. applying a predetermined stimulation pattern to determine the resulting blood pressure parameter (step 104); 3. Determining whether any predetermined stimulation pattern meets the criteria (e.g., meets the allowed slope and error) (step 106); 4. If not, further calculating new stimulation pattern parameters (steps 112, details will be described later), applying the new stimulation pattern parameters to the patient, and determining whether any new stimulation pattern meets the criteria (e.g., based on mean SBP, slope, and error) (step 106); may be included.

[0069] In an embodiment, the effect of the stimulation pattern on blood pressure may be expressed in mmHg by subtracting the mean SBP of the baseline blood pressure from the mean SBP achieved with that pattern. Generally, since any hypertension therapy aims at reducing blood pressure, a more negative numerical value (for the effect) for the stimulation pattern is a better result. However, in some cases, blood pressure reduction may also increase the risk of hypotension and may not be very desirable.

[0070] In an experiment of applying a hypertension-lowering stimulation pattern to a patient, the inventors have found that, in some cases, especially when incorrect pattern parameters are selected for a specific patient, the initial blood pressure drop is not maintained over time and the pressure gradually increases over a period of several minutes. It has been found that an observation period of about 3 minutes is sufficient to determine whether the therapeutic effect is stable over time. In an embodiment, the slope calculated for the hypertension-lowering stimulation pattern represents this level of stability.

[0071] Based on the experiment, the inventors have also found that when using a hypertension therapy stimulation pattern including a periodic stimulation pattern consisting of a plurality of beats with a shorter AV (atrioventricular) delay followed by a plurality of beats with a longer AV delay, 1. Shortening the shorter AV delay usually results in a further drop in systolic blood pressure; 2. Lengthening the longer AV delay usually results in a lower slope. 3. Changing the pacing rate (shorter AV delay and / or longer AV delay) mainly affects the slope, and was found.

[0072] However, there may be some limitations to the values of these parameters.

[0073] In an embodiment where a periodic stimulation pattern is applied consisting of a plurality of beats with a shorter AV (atrioventricular) delay followed by a plurality of beats with a longer AV delay, the shorter AV delay may be in the range of about -5 milliseconds to about 130 milliseconds, and the longer AV delay may be in the range of about 100 milliseconds to about 240 milliseconds.

[0074] In one practical embodiment, a negative AV delay may require predicting a naturally occurring atrial event or ventricular pacing prior to atrial pacing. Thus, in some practical embodiments, the minimum allowable AV delay value is 0 milliseconds.

[0075] A shorter AV delay may be too long to effectively reduce atrial contraction. In an embodiment, the inventors have found that a value of a shorter AV delay of about 130 milliseconds (when pacing both the atrium and the ventricle) is the longest value that can be effectively used.

[0076] AV delay values longer than the natural AV delay mean that before the pacing pulse is triggered, spontaneous ventricular activation begins and may be suppressed (due to natural activation). Even in such cases, the therapy is effective, but the pacing pulse is ineffective. That is, in one embodiment, the associated AV delay value for this method should not be longer than the natural AV delay, except in cases where there is no natural AV delay (e.g., in cases of complete heart block). In some embodiments, for example, the natural AV delay can be used as a longer AV delay by intentionally setting the pacing AV delay longer than the natural AV delay. These embodiments may be relevant to individuals with A-V conduction and may be less relevant to individuals with any level of partial or complete ventricular conduction block.

[0077] In embodiments, since the baroreflex response to blood pressure is usually fast, the longer AV delay heart rate should typically be a maximum of 5. In embodiments, since the time constant of the baroreflex response to a decrease in blood pressure is much longer, the shorter AV delay heart rate should typically be 6 - 18.

[0078] In some embodiments, restrictions on the stimulation parameters ( "parameter restrictions"), restrictions on the AV delay, and restrictions on the heart rate, such as using only shorter AV delays of 0 - 100 milliseconds and only shorter AV delay heart rates of 6 - 18, are used by the embodiments when calculating the stimulation pattern as part of the technique.

[0079] Rarely, a patient may have a time constant of change that is completely different from the ranges suggested here, in which case the present embodiments may not be very effective.

[0080] Based on experiments, the inventors have found that in many cases, finding a stimulation pattern that causes a stable blood pressure response is more difficult than finding a stimulation pattern that has a short-term effect that fades over time. To address that issue, referring to FIGS. 1 and 3, an embodiment of method 100 includes an iterative calculation process for calculating new stimulation pattern parameters in step 112.

[0081] As shown in FIG. 3, the calculation process is started by determining in step 302 whether the stimulation pattern having the best effect (e.g., the largest drop in blood pressure) is sufficiently stable. In that case, the calculation process proceeds to step 304, where the shorter AV delay used in that stimulation pattern is decreased by an increment (e.g., subtracting 10 milliseconds from the value, but not exceeding the parameter limit, which in this case means the value cannot become negative), and then it may be determined whether the decreased shorter AV delay has already been used in method 100. If the stimulation pattern having the decreased shorter AV delay has not yet been used, the calculation process ends and method 100 proceeds to step 114, at which point a new stimulation pattern having the decreased shorter AV delay is applied to the patient and the blood pressure change and effect are determined.

[0082]

[0083] If it is determined in step 304 that the stimulation pattern having the decreased shorter AV delay has already been used, then the calculation process further continues in step 306 by decreasing the shorter AV delay beat count by 1, and then in step 114, a new stimulation pattern is applied to determine the blood pressure change and effect.Referring back to step 302, if the stimulation pattern with the best effect is not sufficiently stable, then the calculation process proceeds to step 308 to find the most stable (e.g., with the smallest slope) stimulation pattern by increasing the longer AV delay used in that pattern by an increment (e.g., adding 10 milliseconds to the value, but not exceeding the parameter limit), and then it may be determined whether the increased longer AV delay has already been used in method 100. If the stimulation pattern with the increased longer AV delay has not yet been used, the calculation process ends and method 100 proceeds to step 114, at which point the new stimulation pattern with the increased longer AV delay is applied to the patient and the blood pressure change and effect are determined.

[0084] In step 308, if it is determined that the stimulation pattern with the increased longer AV delay has already been used, then the calculation process, in step 310, decreases the shorter AV delay by an increment (e.g., subtracting 10 milliseconds from the value, but not exceeding the parameter limit), and then continues in step 114 by applying that new stimulation pattern and determining the blood pressure change and effect.

[0085] As shown in FIGS. 1 and 3, after applying the new stimulation pattern in step 114, method 100 may continue in step 106 by determining whether the new stimulation pattern meets the criteria. If the new stimulation pattern does not meet the criteria, method 100 returns to the calculation process 112 to determine another new stimulation pattern.

[0086] Regarding step 106, meeting the specified criteria may include calculating one or more parameters including the mean systolic measurement, slope, individual error, and / or mean error when determining whether any predetermined stimulation pattern meets the specified criteria and when determining whether any new stimulation pattern meets the specified criteria, and comparing each calculated parameter among the one or more calculated parameters with the allowable range of the values of the calculated parameters.

[0087] In a further embodiment, regarding step 106, meeting the specified criteria may further include calculating a weighted score of the stimulation pattern by multiplying each of one or more parameters (such as mean systolic measurement, slope, individual error, and / or mean error) by a weighting factor of a predetermined parameter when determining whether any predetermined stimulation pattern meets the specified criteria and when determining whether any new stimulation pattern meets the specified criteria, and then comparing the calculated weighted score of the stimulation pattern with the weighted scores of other stimulation patterns and / or a predetermined required minimum weighted score. The weighting factor of the predetermined parameter may reflect the relative importance of the characteristics of the therapy for various patients. In one embodiment, for a patient known to have high blood pressure variability, a lower parameter weight score may be assigned to the individual error or the mean error. In another embodiment, a lower parameter weight score may be assigned to the mean systolic measurement of a relatively mild hypertensive patient compared to another more severe hypertensive patient who may be assigned a higher parameter weight score for mean systolic measurement.

[0088] In an embodiment, method 100 may be configured to repeatedly loop through steps 106, 112, and 114 until a predetermined time and / or a time determined by the user has elapsed. During that time, any stimulation pattern determined to meet the criteria may be included in the next steps 108 and 110. As shown in FIG. 1, method 100 may include an optional step 108 showing the measurement results of the stimulation pattern that meets the criteria. The presented measurement results may include the predetermined stimulation pattern from step 104 and / or the stimulation pattern obtained from the calculation process in step 112. Embodiments may show only the measurement results that meet the criteria, while other embodiments may show all measurement results, including those that meet the criteria and those that do not.

[0089] In an embodiment, the measurement results shown in step 108 may include a list of the various stimulation patterns used, each having a set of calculated parameters, such as one or more of the following: 1. Effect - The average SBP of the baseline blood pressure subtracted from the average SBP achieved with that stimulation pattern. Since most physicians are very familiar with blood pressure differences and how to interpret them, it can be expressed in mmHg.

[0090] 2. Stability - The slope calculated for that stimulation pattern. Since physicians are usually not familiar with the concept of linear approximation, the results may be mapped to a set of discrete values and / or categories. In an embodiment, any negative slope may be designated "very stable", a slightly positive slope may be designated "stable" (e.g., a slope of up to 1 mmHg per minute, and generally, up to 5 mmHg between measurements taken over 5 minutes is allowed), and a steeper slope may be designated "unstable".

[0091] 3. Vibration - The average error calculated for its stimulation pattern. Also, the results may be mapped to a set of discrete values and / or categories. In an embodiment, an average squared error value of less than 2 may be designated as "very accurate", an average squared error value of 2 or more and 4 or less may be designated as "relatively accurate", and an average squared error value exceeding 4 may be designated as "relatively inaccurate".

[0092] Alternatively, or optionally, an "effect" parameter can be calculated using an updated baseline measurement. A period without providing stimulation to the patient may precede stimulation delivery. The measurement of systolic blood pressure during this preceding period may be subtracted from the average SBP of the baseline blood pressure performed in the first step 102 of method 100, or alternatively, from the average SBP achieved with that stimulation pattern. Optionally, or additionally, a period without stimulation to the patient may follow stimulation delivery. The measurement of systolic blood pressure during this subsequent period may be averaged and subtracted from the average SBP achieved with that stimulation pattern, instead of subtracting the average SBP of the baseline blood pressure performed in the first step 102 of method 100. Optionally, measurements from periods without stimulation before and after stimulation delivery may be averaged and subtracted from the average SBP achieved with the stimulation pattern to calculate the effect parameter.

[0093] Embodiments may also include provisions such as the updated baseline measurements described above to account for changes in a patient's blood pressure caused by methods of setting up, customizing, and optimizing a blood pressure lowering stimulation therapy such as method 100 of FIG. 1. In an experiment conducted according to method 100, the application of multiple blood pressure regulation stimulation patterns to a patient resulted in a change in the patient's baseline blood pressure for at least a short period during the successive activation of the treatment stimulation pattern as part of the setup, customization, and optimization process. These changes may account for an intermittent and / or short-term gradually decreasing blood pressure, but in embodiments, there may also be an opposite effect where the patient's blood pressure increases over time. The increase may be due to the patient gradually becoming excited or frustrated as a result of the setup process and the blood pressure measurements taken during that process. However, regardless of the reason, experiments have demonstrated that the baseline blood pressure of the underlying patient may change over time in a negative, positive, or no (meaning the blood pressure remains approximately the same) manner.

[0094] To account for this possible movement of the baseline blood pressure over time, i.e., drift, embodiments may determine the blood pressure before and / or after activation of the therapy (before and / or after application of the stimulation pattern), and during rest when no activation is present. Determining the blood pressure may include one measurement or may include multiple measurements to increase accuracy. In embodiments, two measurements are taken and the average of the two measurements is used. If more than two measurements are used, subsequent measurements may be weighted more in the average as any residual effects from the last activation gradually decrease over time. Thus, in embodiments, blood pressure changes and effects may be determined each time based on the most recent and thus accurate baseline blood pressure value.

[0095] The procedure of FIG. 8 shows one embodiment of method 800 for taking into account changes in a patient's blood pressure when applying a stimulation pattern and determining blood pressure changes and effects, which may be performed as part of steps 104 and 114 of method 100 of FIG. 1.

[0096] As shown in FIG. 8, method 800 may begin in step 801 by determining the patient's first baseline blood pressure parameter during a period when it is not activated and prior to the first stimulation pattern. Referring to FIGS. 1 and 8, the determination prior to the stimulation in step 801 may be made in step 102 for the preparation of the first predetermined stimulation pattern applied in step 104, or in step 112 or step 114 for the preparation of the first stimulation pattern applied in step 114.

[0097] As shown in FIG. 8, method 800 may continue in step 802 by applying the first stimulation pattern and measuring the blood pressure during the application of the first stimulation pattern. Referring to FIG. 1, this first stimulation pattern may be the first predetermined stimulation pattern of the first predetermined stimulation pattern in step 104, or the first stimulation pattern of the newly calculated stimulation pattern in step 114.

[0098] After applying the first stimulation pattern, method 800 may continue in step 804 by determining a first baseline blood pressure parameter of the patient during a period when it is not activated. In an embodiment, the first baseline blood pressure parameter is measured by measuring the patient's blood pressure after the application of the first stimulation pattern and when the therapy is not activated, and using the measured post-stimulation blood pressure and the pre-stimulation blood pressure determined in step 801 to calculate the first baseline blood pressure parameter. In an embodiment, the blood pressure may be measured during periods when it is not activated before (pre-stimulation) and after (post-stimulation) each stimulation pattern, and the baseline blood pressure may be calculated using both the pre-stimulation and post-stimulation blood pressure measurements. When multiple stimulation patterns are applied, an embodiment may use blood pressure measurements taken between consecutive stimulation patterns to calculate baseline blood pressure parameters for both the preceding stimulation pattern (as post-stimulation blood pressure) and the subsequent stimulation pattern (as pre-stimulation blood pressure).

[0099] Thus, in an embodiment, the baseline blood pressure (i.e., the blood pressure when the therapy is not activated) may be measured before and after all activations including the first activation (e.g., step 802). The baseline level of therapy activation required to calculate the effect of the therapy activation may be calculated using both the pre-stimulation blood pressure measurement taken before the therapy activation and the post-stimulation blood pressure measurement taken after the therapy is turned off. In the case of multiple therapy activations, the second period of post-stimulation measurement for therapy activation is such that the blood pressure measurements taken during each period when it is not activated during the therapy activation are also pre-stimulation measurements for the next therapy activation (up to the last therapy activation) so that they can be used to calculate the baseline blood pressure parameters for both of the two therapy activations (the activation before which the blood pressure measurement is taken and the activation after which it is taken).

[0100] Referring back to step 804, in an embodiment, the first baseline blood pressure parameter may be determined by calculating the average of blood pressure parameter measurements taken before (step 801) and after (step 804) the application of the first stimulation pattern (step 802). In an embodiment where the measurements are averaged, the measured blood pressure parameters may be weighted so that more recent measurements have a higher weight because any residual effects from the last activation gradually decrease over time.

[0101] The method 800 may then continue in step 806 by determining the blood pressure changes and effects caused by the first stimulation pattern relative to the first baseline blood pressure parameter. For example, the effect may be determined by calculating the difference between the measured blood pressure of step 802 and the first baseline blood pressure. Referring to FIGS. 1 and 8, the first baseline blood pressure parameter may be determined from the baseline blood pressure parameters measured at step 801 (before stimulation) and step 804 (after stimulation) for the first predefined stimulation pattern applied at step 104, or the first stimulation pattern newly calculated at step 114.

[0102] After determining the blood pressure changes and effects for the first stimulation pattern, the method 800 may continue in step 808 by applying a second stimulation pattern and measuring the blood pressure during the application of the second stimulation pattern. Referring to FIG. 1, this second stimulation pattern may be the second predefined stimulation pattern of the first predefined stimulation pattern of step 104, or the second stimulation pattern of the newly calculated stimulation pattern of step 114.

[0103] After applying the second stimulation pattern, method 800 may continue in step 810 by determining the patient's second baseline blood pressure parameter during the period when it is not activated. In an embodiment, the second baseline blood pressure parameter is measured when the application of the second stimulation pattern ends and the therapy is not activated, and the measured post-stimulation blood pressure and the pre-stimulation blood pressure determined in step 804 (which was the post-stimulation blood pressure for the first stimulation pattern) are used to calculate the second baseline blood pressure parameter. In an embodiment, the second baseline blood pressure parameter may be determined by calculating the average of the blood pressure parameter measurements taken before (step 804) and after (step 810) the application of the second stimulation pattern (step 808). In embodiments where the measurements are averaged, the measured blood pressure parameters may be weighted so that more recent measurements have a higher weight because any residual effects from the last activation gradually decrease over time.

[0104] Method 800 may then continue in step 812 by determining the blood pressure changes and effects caused by the second stimulation pattern relative to the second baseline blood pressure parameter determined in step 810. For example, the effect may be determined by calculating the difference between the measured blood pressure in step 808 and the second baseline blood pressure.

[0105] Method 800 may then continue iteratively in the same manner as shown in step 814, repeating steps 808, 810, and 812 for any remaining stimulation patterns. Thus, in an embodiment, the most recent baseline blood pressure parameter is used each time the blood pressure changes and effects are determined for a stimulation pattern.

[0106] According to the embodiment of FIG. 8, the patient may have a first baseline systolic blood pressure of 142 mmHg based on the measurements taken at step 801 (before the application of the first stimulation pattern, i.e., “activation”) and step 804 (after the application of the first stimulation pattern). Referring to steps 802 to 806, after applying the first stimulation pattern and measuring a systolic blood pressure of 132 mmHg during the application of the first stimulation pattern, a blood pressure change of -10 mmHg may be determined based on the difference between the first baseline systolic blood pressure of 142 mmHg and the measured systolic blood pressure of 132 mmHg.

[0107] Then, referring to step 808, a second stimulation pattern may be applied, and a systolic blood pressure of 134 mmHg may be measured during the application of the second stimulation pattern.

[0108] Then, referring to step 810, after applying the second stimulation pattern and during a period when it is not activated, the measurements taken before (step 804, which is also the measured post-stimulation blood pressure parameter for the first stimulation pattern) and after (step 810) the application of the second stimulation pattern may indicate that the baseline systolic blood pressure of the patient without therapy rises to 146 mmHg. The elevated baseline systolic blood pressure may be designated as the second baseline blood pressure parameter.

[0109] Therefore, referring to step 812, the effect of the second stimulation pattern may be determined to be a blood pressure change of -12 mmHg based on the difference between the second baseline blood pressure parameter of 146 mmHg and the systolic blood pressure of 134 mmHg measured during the application of the second stimulation pattern. Therefore, the blood pressure drop of the second stimulation pattern is greater than that of the first stimulation pattern.

[0110] Next, referring to step 814, after determining the blood pressure change and effect of the second stimulation pattern, method 800 measures a systolic blood pressure drop of 130 mmHg during the application of the third stimulation pattern, and based on the measurements before (step 810, which is also the measured post-stimulation blood pressure parameter for the second stimulation pattern) and after the application of the third stimulation pattern during the non-activated period, determines a third baseline blood pressure of 139 mmHg, and based on the difference between the third baseline blood pressure parameter of 139 mmHg and the systolic blood pressure of 130 mmHg measured during the application of the third stimulation pattern, determines that the effect of the third stimulation pattern is a blood pressure change of -9 mmHg, and may continue by repeating steps 808 to 812 for the third stimulation pattern. Thus, the blood pressure drop of the third stimulation pattern is smaller than both the blood pressure drops of the first and second stimulation patterns.

[0111] Alternatively, as described in the embodiment of FIG. 8, instead of using both pre-stimulation and post-stimulation measurements to determine the baseline blood pressure parameter, in other embodiments, the blood pressure parameter may be measured after the application of the stimulation pattern, and the baseline blood pressure parameter may be determined by using these measured post-stimulation blood pressure parameters instead of the pre-stimulation baseline blood pressure parameter measured before the stimulation pattern. For example, in FIG. 8, the second baseline blood pressure parameter may be determined by measuring the blood pressure parameter after the application of the second stimulation pattern (at step 810) and using these measured post-stimulation blood pressure parameters instead of the measured pre-stimulation blood pressure parameter of step 804.

[0112] In another alternative embodiment, only pre-stimulation measurements may be used to determine the baseline blood pressure parameter, without using post-stimulation measurements. For example, in FIG. 8, the second baseline blood pressure parameter may be determined based on the measured pre-stimulation blood pressure parameter at step 804 before the application of the second stimulation pattern, and any measured post-stimulation blood pressure parameter after the application of the second stimulation pattern may not be considered.

[0113] In another alternative embodiment, during the period when it is not activated and before the application of the first stimulation pattern, the patient's initial baseline blood pressure parameters may be determined, and these initial baseline blood pressure parameters may be used to determine the blood pressure changes and effects for two or more stimulation patterns. By this approach, it may be possible to avoid measuring blood pressure parameters between stimulation patterns, thereby simplifying and / or accelerating the process, and reducing the resources (such as battery power) required to complete the process. In an embodiment, the initial baseline blood pressure parameters are determined once before the application of the first stimulation pattern during the period when it is not activated, and then may be used to determine the blood pressure changes and effects for the first stimulation pattern and all subsequent stimulation patterns.

[0114] In an embodiment, the initial baseline blood pressure parameters may be completely overlooked, prioritizing measurements according to each subsequent stimulation pattern applied. However, as described above, in other embodiments, each of the measurements may be considered, for example, by averaging with or without weighting. In one embodiment, the "off" measurements taken after the application of the stimulation pattern and during the period when it is not activated may be used as the average of the "off" measurements taken immediately before the stimulation pattern and the measurements taken after the stimulation pattern to calculate the updated baseline blood pressure parameter for each stimulation pattern.

[0115] Referring again to FIG. 1, optionally, step 108 may include provisions for simplifying the determination of an optimal stimulation pattern for a patient, which may be particularly useful when a healthcare professional is determining an optimal stimulation pattern for the patient. In an embodiment, in step 108, 1. In a previous step of method 100, selecting the best stimulation pattern (e.g., a set of stimulation parameters) for the patient. Thus, the best stimulation pattern may identify the one having the best effect among "highly stable" patterns, or among "stable" patterns if there are no "highly stable" patterns, or among "unstable" patterns if there are no "highly stable" or "stable" patterns, and 2. Removing the best stimulation pattern from the result table and selecting a second best stimulation pattern applied to the patient in a previous step of method 100 by performing the same selection process as in the selection in 1, and 3. Re-applying the best stimulation pattern and the second best stimulation pattern to the patient and presenting only the results of these two stimulation patterns to the healthcare professional for therapy determination, which may show a smaller set for potential selection of stimulation parameters for therapy.

[0116] As shown in FIG. 1, once the measurement results have been determined (and optionally shown in step 108), method 100 continues in step 110 by determining an optimal stimulation pattern for a particular patient. That determination may be made by a user (e.g., a healthcare professional), or may be automatically completed, for example, by an automated computer-implemented evaluation of the measurement results according to the processes and criteria described herein.

[0117] Once the optimal stimulation pattern is determined, method 100 may then proceed to the final step 116 where the optimal stimulation pattern is applied to a particular patient. In an embodiment, the optimal stimulation pattern may be initiated by a user (e.g., a healthcare professional). In another embodiment, if the determination in step 110 is completed automatically, the application of the optimal stimulation pattern to the patient may also be completed automatically, e.g., by the application of the stimulation pattern by an automated computer.

[0118] In embodiments of steps 110 and 116, if the stimulation pattern having the maximum SBP lowering effect is "very stable", it will likely be an appropriate choice for many patients, except when the lowering is so large as to raise concerns about hypotension. For example, this could occur if, on the day the parameter setting procedure was performed, the patient was not taking all of the patient's hypertension medications. If the stimulation pattern having the maximum SBP lowering effect is not "very stable", determining the optimal stimulation pattern parameters for the patient (e.g., by either a healthcare professional or the application of an automated computer implementation) may depend on a comparison between the maximum BP lowering effect of the pattern having the best stability achieved (if "very stable") and the maximum BP lowering effect of the pattern having the next best stability achieved (if any pattern achieved "very stable", "stable"; if at least one pattern achieved "stable", "unstable"). In some cases, it may be preferable to apply a more unstable pattern that has a greater BP lowering effect. For example, in the case of a hypertensive patient with an SBP of 153 mmHg, it may be better to apply a "stable" pattern that achieves a 23 mmHg drop in SBP than a "very stable" pattern that achieves only an 11 mmHg drop.

[0119] In some embodiments, the actual slope calculated for each stimulation pattern (not or in addition to the designation of "very stable", "stable" or "unstable") may be used to determine the optimal pattern to be applied to the patient. In further embodiments, the average error calculated for each pattern may also be used to determine the pattern to be applied. Such determination may be based on a score-based determination mechanism. For example, a weight function that assigns a numerical value for each possible value of the calculated parameter may be applied to the calculated parameters. The weights of the different calculated parameter values for each pattern may be multiplied to determine the score for that pattern, and the pattern with the highest score may be applied to the patient. Examples of weight functions include that the weight of the effect is three times its absolute value (since this may be the most clinically important aspect), the weight of the slope is the value of the negative slope (since a linear approximation line of the negative slope is generated by the desired decrease in BP measurement), and / or the weight of the average error is one divided by the error (thus the smaller the error, the more advantageous).

[0120] Blood pressure measurements can vary for a variety of reasons, related to the inaccuracies inherent in the various measurement devices available, and to physiological changes (such as respiration, coughing, sneezing, cardiac arrhythmias, etc.) that can affect blood pressure at the moment of measurement. Thus, embodiments may include provisions for dealing with measurement anomalies. For example, embodiments may include additional steps for correcting measurement outliers when sufficient measurements are available (e.g., at least three). Embodiments may add a step of correcting measurement outliers when calculating any pattern parameters (e.g., mean SBP, slope, and error) to prevent miscalculation due to such outliers. In an embodiment, measurement outliers may be identified by examining a list of errors calculated for each measurement obtained for a pattern. If one of the errors is significantly larger than any of the others (e.g., at least twice as large as the remaining errors), the calculation of the parameters (e.g., mean SBP, slope, and error) for this pattern should be repeated, omitting the measurement associated with the large error. Other methods for detecting outliers may be used to remove these outliers. In an embodiment, removing outliers may lead to the identification of a more appropriate stimulation pattern for the patient, particularly if the process includes more steps for calculating stimulation parameters.

[0121] To further illustrate method 100 of FIG. 1, each of the tables of FIGS. 4 - 6 provides measurement results for one embodiment of method 100 using a hypertensive therapy stimulation pattern that includes a periodic stimulation pattern consisting of a plurality of beats with a shorter AV delay followed by a plurality of beats with a longer AV delay.

[0122] Referring to FIG. 4, a method for customizing a blood pressure lowering stimulation therapy was performed on a patient using a blood pressure measuring device that could only obtain the value of systolic blood pressure every about one minute. Depending on the time assigned to the customization process, it was possible to perform five measurements for each repetition of the applied stimulation pattern. The healthcare professional determined that a 10 mmHg drop was desirable for a particular patient.

[0123] As shown in Table 1 of FIG. 4, the row titled "Baseline" shows the value of the systolic blood pressure measured without applying the therapy, according to step 102 of method 100. For example, measurement number 1 was taken 1 minute and 4 seconds after the time considered as the "start" of the baseline, and the measured systolic blood pressure was 135 mmHg. The next measurement was taken 1 minute and 1 second later, i.e., 2 minutes and 5 seconds after the "start" of the baseline measurement, and the measured systolic value was 137 mmHg. The average systolic blood pressure level of the five measurements taken was 135 mmHg.

[0124] According to step 104 of method 100, in the embodiment, there are three predefined sets of stimulation parameters applied to the patient. In Table 1 of FIG. 4, the therapy parameters used are shown in the appropriate rows to the right of the column of therapy pattern numbers. The three predefined sets of stimulation parameters are pattern numbers 1, 2, and 3. Thus, for example, therapy parameter set number 1 applies a 60-millisecond AV delay (shorter AV delay value) for 13 consecutive beats, then a 160-millisecond AV delay (longer AV delay value) for 3 beats, then cycles back and applies a 60-millisecond AV delay for 13 beats, and so on. In therapy parameter set number 2, a 30-millisecond AV delay (shorter AV delay value) is applied for 7 consecutive beats, then a 140-millisecond AV delay (longer AV delay value) is applied for 1 beat, then cycles back and applies a 30-millisecond AV delay for 7 beats, and so on. Therapy parameter set number 3 applies a 50-millisecond AV delay (shorter AV delay value) for 11 consecutive beats, then a 160-millisecond AV delay (longer AV delay value) for 2 beats, then cycles back and applies a 50-millisecond AV delay for 11 beats, and so on. The measurement times and systolic values measured when each of the three predefined stimulation patterns was applied to the patient are also listed in Table 1 of FIG. 4.

[0125] Referring to step 106 of FIG. 1, in this embodiment, since none of the first three predetermined stimulation patterns achieved a 10 mmHg drop, method 100 proceeded to step 112 to calculate another set of parameters (another stimulation pattern). When step 302 (see FIG. 3) of the calculation process 112 was implemented, the stimulation pattern that achieved the best effect was pattern 1 (-7.4 mmHg), but it was not "very stable" and was only "stable". Therefore, when transitioning to step 308 of the calculation process 112, since the most stable pattern was pattern 2 (stability -0.78), the next pattern (assigned to pattern number 4) may be based on pattern 2 that has a larger value for a longer AV delay than pattern 2. Assuming an AV delay increment of 10 milliseconds, in pattern 4, instead of the value of 140 milliseconds used in pattern 2, it may be possible to use a longer AV delay value of 150 milliseconds. A pattern that applies an AV delay of 30 milliseconds (shorter AV delay value) for 7 consecutive values and then an AV delay value of 150 milliseconds (longer AV delay value) for 1 beat has not yet been used in this customization process. Then, following the "no" branch of step 308, that pattern was used as pattern number 4 and applied to the patient.

[0126] The measurements taken when stimulation pattern 4 was applied to the patient are listed in the relevant row of Table 1 in FIG. 4. Then, all four available stimulation pattern results were reconsidered as part of step 106 of method 100. Unfortunately, none of the four patterns achieved the desired 10 mmHg blood pressure drop, so another stimulation pattern was calculated and applied. When step 302 of calculation process 112 was performed, the stimulation pattern that achieved the best effect was next pattern number 4, which was also "very stable" with a stability of -0.49. Thus, according to step 304 of calculation process 112, by reducing the shorter AV delay value used at pattern number 4 by 10 milliseconds, a pattern was obtained that applied a 20 millisecond AV delay (shorter AV delay value) for 7 consecutive values and then a 150 millisecond AV delay (longer AV delay value) for 1 single beat, which had not yet been used in the process. Thus, following the "no" branch of step 304, that pattern was applied as pattern number 5.

[0127] The measurements taken when stimulation pattern 5 was applied to the patient are listed in the relevant row of Table 1 in FIG. 4. The desired effect (a 10 mmHg drop) has not yet been achieved by any of the applied parameter patterns, but in this embodiment, the time allotted for the execution of the customization process has ended and the process was stopped at that point. In such a situation, the embodiment may consider that the decision process of step 106 has timed out and may consider the measurements not to meet the criteria for the next steps 108, 110, and 116.

[0128] Table 2 in FIG. 5 shows a simplified format for presenting customization results according to one embodiment. This simplified presentation may be useful for a healthcare professional to determine, according to step 110 of method 100, that pattern 4 is optimal for this patient.

[0129] In Table 1 of FIG. 4, the systolic blood pressure value obtained in the third measurement (time 3 minutes and 5 seconds) of stimulation pattern 3 is 141 mmHg. Since this value far exceeds the other values of 125, 124, 126, and 123 mmHg in pattern 3, it can be pointed out that it is an outlier. By identifying and removing this outlier from the calculation of the effect and stability of stimulation pattern 3 (shown in Table 3 of FIG. 6), the effect becomes -10.50 mmHg and the stability becomes -0.19, which is sufficient to meet the acceptable criteria. Therefore, for this embodiment, using the embodiment of method 100 in which measurement outliers are removed from the calculation means that the customization method 100 stops after the application of the first three predetermined stimulation patterns, proceeds to steps 104, 106 (conditional on "yes"), and 108, and does not require the calculation and application of new stimulation patterns in steps 112 and 114.

[0130] In some embodiments, for example, when using a non-invasive continuous blood pressure measurement device such as the Caretaker Medical VitalStreams (trademark) device manufactured by Caretaker Medical (trademark) of Charlotte, North Carolina, systolic and diastolic blood pressure data for each heartbeat are available. It is still possible to apply a method as described above to calculate the average systolic measurement value, slope, and error using a plurality of separate blood pressure measurement values obtained during the stimulation activation time. However, if necessary for the method, in another embodiment, better or additional calculations can be performed using the systolic and diastolic blood pressure values obtained immediately before, during, and immediately after (where "immediately" is typically 0 to 300 seconds) to improve the determination regarding the next set of stimulation parameters to be applied.

[0131] When applying a stimulation pattern consisting of short AV delay beats followed by long AV delay beats (as a repeating periodic pattern), as expected by the additional filling that occurs during the longer AV delay period, the short AV delay beats produce a lower systolic blood pressure value than the long AV delay beats, and it has been observed by the inventors that they cause a higher blood pressure in accordance with the Frank-Starling law. Thus, a time series list of systolic blood pressure measurements obtained during the application of such a stimulation pattern may be separated based on the known number of short AV delay beats and long AV delay beats, supported by the expected differences in the measured systolic blood pressure values in these different beats. Thus, embodiments may generate two sub-lists containing beats occurring at different times (one a sub-list of short AV delay systolic values and the other a sub-list of long AV delay systolic values).

[0132] In some embodiments, the average SBP (systolic blood pressure) value of the stimulation may be calculated using only the short AV delay sub-list SBP values. Since there are dozens of short AV delay beats during a period from 3 minutes to 10 minutes, such an average calculation is expected to be more accurate than a calculation based on only a few SBP values. In some embodiments, a more accurate slope of the stimulation may be calculated using only the SBP values of the short AV delay sub-list.

[0133] To further assist in the determination of parameter changes, parameters within and between cycles may be calculated. One such parameter may be the difference between the last SBP value in a short AV delay beat series and the first SBP value in the next short AV delay beat series. Preferably, a list of all these differences calculated for the entire cycle of the transmitted stimulation should be considered. The first SBP in the next series should be lower than the last SBP in the previous series throughout the stimulation period, but the inventors have observed that in patients, it generally starts large and decreases over time. If this parameter does not function as expected, the number of long AV delay beats can be increased, the long AV delay can be increased, or both can be done.

[0134] Another such parameter is the difference between the first SBP value and the last SBP value in a series of short AV delay beats. Preferably, a list of all these differences calculated for all cycles of the delivered stimulus should be considered. The first SBP value must be lower than the last SBP value in that series throughout the stimulation period, but the inventors have observed that in patients, that difference decreases over time. If this parameter does not function as expected, the number of short AV delay beats can be increased, the duration of the short AV delay can be shortened, or both can be done.

[0135] Yet another such parameter is the difference between the first SBP value and the last SBP value in a series of long AV delay beats. Preferably, a list of all these differences calculated for all cycles of the delivered stimulus should be considered. The first SBP value should be higher than the last SBP value in that series throughout the stimulation period, but the inventors have observed that that difference decreases over time. If this parameter does not function as expected, the number of long AV delay beats can be increased, the duration of the long AV delay can be lengthened, or both can be done.

[0136] Another such use that may be considered involves examining for an overshoot in the event that one exists when activation is stopped. The overshoot is the difference (if any) between the SBP value of the first beat immediately following the end of the stimulus and the baseline value of the SBP. Experiments by the inventors have shown that when the stimulation activation is shorter than 10 minutes, the baseline SBP value typically returns within less than 1 minute. For purposes of calculation, the average SBP value of the first 5 beats after the stimulus has ended can be compared to the average SBP over the period of 5 seconds to 300 seconds after the end of the stimulus. In embodiments, a negative or very small overshoot value is desirable, which means that the average SBP of the first 5 beats must be lower than or equal to the average SBP over the period of 5 to 300 seconds after the end of the stimulus. Otherwise, the number of long AV delay beats can be increased, the long AV delay can be increased, and / or the duration of the short AV delay beats can be increased.

[0137] In some embodiments, the optimization of the therapy may be performed once at the start of the therapy for the patient. In another embodiment, additional optimizations may be performed periodically (e.g., every 12 months) to account for changes in the patient's physiological functions or changes in the drug regimen. In some embodiments, the optimization is performed when the patient's systolic blood pressure exceeds a predetermined high level (e.g., 135 mmHg) over a minimum period (e.g., 3 days), or when it exceeds a minimum percentage of the measurements over the minimum period (e.g., 80% of the measurements over 4 days). Similarly, the optimization is performed when the patient's systolic blood pressure drop falls below a predetermined low level (e.g., 100 mmHg) over a minimum period (e.g., 4 days), or when it falls below a minimum percentage of the measurements over the minimum period (e.g., 70% of the measurements over 5 days). Embodiments may measure blood pressure to determine the need for optimization as described above using, for example, an implantable blood pressure monitor, an external blood pressure monitor (e.g., a wearable watch), and / or any other suitable blood pressure measuring device (e.g., as shown by the blood pressure measuring device 62 of FIG. 7 described below).

[0138] In some embodiments, separate optimization processes may be performed for different conditions such as time of day, the patient's activity level, and / or heart rate. For example, the patient may be made to walk on a treadmill to increase the activity level and heart rate. Under different conditions (such as time of day or the patient's activity level), different parameter sets may be optimal. In some embodiments, if different optimization results are determined for different patient conditions, different therapy parameters (found by optimization) may be used when different patient conditions (such as time of day or activity level) are detected.

[0139] In an embodiment where blood pressure data and optimization are repeatedly performed over time, the set of predefined stimulation patterns may be changed over time according to the actual optimization results obtained from the patient. In one embodiment, the optimal set of parameters obtained in a previous optimization may be used as one of the predefined stimulation patterns in the current optimization. The calculation leading to the new stimulation parameters may also be affected by the patient response to the parameter changes in the previous optimization process. In one embodiment, if in the past a particular shortening of the short AV delay resulted in a moderate blood pressure drop, a greater shortening of the short AV delay may be used in the next optimization process. The criteria for determination may also be changed. In one embodiment, if the patient response to the stimulation parameters has a steeper slope or a greater error, the steeper slope or greater error may still be considered acceptable.

[0140] In an embodiment where blood pressure data and optimization are repeatedly performed over time, the change in the patient response to the stimulation pattern can generate relevant clinical data for the physician treating the patient. In one embodiment, an increase (over time) in blood pressure as a response to the same stimulation pattern may indicate a deterioration in the patient's condition. In another embodiment, an increase in the error (blood pressure change) for the same stimulation pattern, or the average error across different stimulation patterns, may indicate an increase in blood pressure variability.

[0141] This embodiment may also include provisions for implementing the methods described herein, including systems and devices. The systems and devices may include medical systems and devices for monitoring a patient's physiological state and / or delivering therapy. The devices may be embedded and / or incorporated, for example, in an external medical device including a wearable medical device. For example, some implantable medical devices (IMDs) may use one or more elongated electrical leads carrying stimulation electrodes, sensing electrodes, and / or other sensors. The IMD may deliver therapy to, or monitor the state of, various organs, nerves, muscles, or tissues such as the heart, brain, stomach, spinal cord, pelvic floor, etc. The implantable medical leads may be configured to place electrodes or other sensors at desired locations for delivery of electrical stimulation or sensing of physiological states. The electrodes or sensors may be located, for example, at the distal portion of a lead placed subcutaneously, transvenously, or submuscularly. The proximal portion of the lead may be coupled to an implantable medical device processing unit including electronic circuits such as signal generation electronic circuits and / or sensing electronic circuits.

[0142] The embodiment may use an implantable medical device such as a cardiac pacemaker or an implantable cardioverter defibrillator (ICD) capable of providing therapeutic electrical stimulation to a patient's heart using the signal generation electronic circuits of a pacemaker or ICD that deliver stimulation through the electrodes of one or more implantable leads. The lead may be transvenous (e.g., advanced through a vein and placed in contact with heart tissue) or a non-transvenous lead implanted outside the heart (e.g., epicardially, endocardially, or subcutaneously). In an embodiment, the electrodes may be used to detect intrinsic cardiac electrical signals for monitoring the rhythm of the heart and to deliver electrical stimulation pulses to the heart according to a desired therapy.

[0143] FIG. 7 shows a system 700 for customizing and optimizing a blood pressure drop stimulation therapy, including a stimulation device 41, a control circuit 40, one or more sensors 470, and one or more electrodes 49, according to one embodiment. The system 700 may be constructed and have components similar to those of a cardiac pacemaker, which are essentially known in the art, as described herein. Optionally, one or more parts of the system 700 may be implantable. Optionally, the system 700 may include components capable of providing additional and / or alternative electrical therapies for the heart (such as defibrillation). A part of the system 700 may be configured, optionally with some modifications as known in the art for implantable pacemakers, to be essentially implanted in a patient's body, as described herein.

[0144] In an embodiment, the system 700 may also include an external controller 60 that communicates with the stimulation device 41. The external controller 60 may be configured to, for example, receive data from the stimulation device 41, process the data, and control the operation of the stimulation device 41. The external controller 60 may also receive inputs from other system components and / or the user via a user interface. The external controller 60 may include, for example, a display for requesting and receiving inputs from the user and for displaying measurement results and the status of the operation of the stimulation device 41.

[0145] In an embodiment, the system 700 may also include a blood pressure measurement device 62 as described above. The blood pressure measurement device may communicate with the external controller 60 and / or the stimulation device 41 and may provide blood pressure measurement data.

[0146] The stimulation device 41 may include a biocompatible body 39, one or more controllers 42, a power source 43, a clock 44, a memory 45, and a telemetry unit 46. The body 39 may comprise a housing for accommodating the plurality of components of the system. The controller 42 may be configured to control the operation of the system and may implement any of the embodiments and methods disclosed herein. In one embodiment, the controller 42 may control the delivery of stimulation pulses, the determination of a predefined stimulation pattern, the calculation of a new stimulation pattern, the measurement and recording of blood pressure results, the communication of the measured blood pressure results for presentation of the results, the determination of the most suitable stimulation pattern for the patient, and / or the application of the optimal stimulation pattern to the patient. In an embodiment, the controller 42 may receive signals from sensors, record the signals as data in the memory 45, and communicate the data using the telemetry unit 46.

[0147] In some embodiments, the power source 43 may include a battery. In an embodiment, the power source 43 may include a rechargeable battery. In some embodiments, the power source 43 may include a battery rechargeable by induction.

[0148] In some embodiments, the telemetry unit 46 may be configured to communicate with one or more other units and / or components, for example by wireless telemetry. In an embodiment, the telemetry unit 46 may be configured to communicate with an external controller 60, which may be configured to program, for example, the controller 42 and / or the memory 45, receive data from the telemetry unit 46, and / or facilitate the display of the data directly or by generating signals for the operation of a separate display. The telemetry unit 46 may also be configured to communicate with a blood pressure measurement device 62.

[0149] In an embodiment, the blood pressure measuring device 62 and the external controller 60 may be combined in a single device. The blood pressure measuring device may be part of the stimulating device 41.

[0150] In some embodiments, the system 700 may include one or more sensors 470 for detecting a patient's condition. The sensors may be integrated with, attached to, and / or connectable to the system 700. In an embodiment, as shown in FIG. 7, the system 700 may include one or more atrial sensors 47 for detecting the onset of atrial excitation and / or one or more sensors 48 for providing other feedback parameters (e.g., blood pressure related parameters). In some embodiments, the sensor 48 may comprise one or more pressure sensors, electrical sensors (e.g., ECG monitoring), flow sensors, heart rate sensors, activity sensors, and / or component sensors. The sensor 48 may include mechanical sensors and / or electronic sensors (e.g., ultrasonic sensors, electrodes, and / or RF transceivers). In some embodiments, the sensor 48 may communicate with the telemetry unit 46 of the device 41 via telemetry. In some embodiments, the system 700 may include one or more sensors for detecting one or more feedback parameters for applying and / or controlling the magnitude of the AV delay.

[0151] In an embodiment, for example, the system 700 may include one or more electrodes 49 capable of applying cardiac pacing. The electrodes 49 may be integrated with, attached to, and / or connectable to the system 700. In some embodiments, the electrode 49 may include a ventricular electrode 791 configured to pace at least one ventricle. Further, the system 700 may include one or more atrial electrodes 792 for pacing one or more atria.

[0152] In some embodiments, the ventricular electrode 791 and / or the atrial electrode 792 may be standard pacing electrodes. The ventricular electrode 791 may be positioned relative to the heart at a location known in the art for ventricular pacing. For example, the ventricular electrode may be disposed inside and / or near one or more ventricles. In some embodiments, the atrial electrode 792 may be disposed inside and / or near one or more atria. In some embodiments, the atrial electrode 792 may be attached to one or more atria at one or more positions selected to provide early detection of atrial excitation or depolarization. For example, in some embodiments, the atrial electrode 792 may be attached to the right atrium near the location of the sinoatrial (SA) node.

[0153] One location of the ventricular electrode 791 may be such that pacing can reduce or minimize the QRS prolongation when the heart is paced, in order to reduce or minimize asynchrony. In some embodiments, this location is near the His bundle of the ventricular septum, near the left bundle branch, or in the region of the left bundle branch, such that the left bundle branch is captured when paced. The ventricular electrode 791 may additionally or alternatively be disposed on the epicardium or coronary vein of the heart. Optionally, to reduce asynchrony, two or more electrodes may be disposed in the ventricles to provide bi-ventricular or multi-site pacing. Additionally or alternatively, when performing bi-ventricular pacing, a third lead may be used to pace the left ventricle in parallel or with a fixed delay from right ventricular pacing.

[0154] The stimulation device 41 may include a pulse generator or a stimulation circuit configured to deliver a stimulation pulse to at least one heart chamber. The pulse generator or stimulation circuit may include some or all of the standard capabilities of a conventional pacemaker. One or more controllers 42 may be configured to control the pulse generator or stimulation circuit. The atrial electrode 792 (and optionally other electrode sensors configured to sense other heart chambers) may be connected to the system 700 via a particular circuit that amplifies the electrical activity of the heart and enables sampling and detection of the activation of a particular chamber. Other circuits may be configured to deliver stimulation to a particular electrode to pace the heart and generate propagating electrical activations.

[0155] In some embodiments, one or more additional sensors 48 may be disposed within or on one or more atria and / or within or on one or more ventricles and / or within or on one or more other locations that may optionally be adjacent to the heart. In embodiments, one or more sensors 48 may be disposed on and / or within one or more large veins and / or on and / or within one or more arteries and / or on and / or within one or more heart chambers. These sensors 48 may measure pressure or other metrics such as impedance and / or flow, for example.

[0156] In some embodiments, one or more controllers 42 may comprise a microprocessor powered by a power supply 43 or may be a microprocessor. In some embodiments, the stimulation device 41 may comprise, for example, a crystal-generated clock 44. The stimulation device 41 may comprise an internal memory 45 and / or may be connected to an external memory. In an embodiment, the device may be connected to an external memory via a telemetry unit 46. In some embodiments, the telemetry unit 46 may be configured to enable communication with external devices such as one or more of a programmer and / or sensor 48. Any and all feedback information and / or logs of the operation of the device may be stored in the internal memory 45 and / or relayed to an external memory unit by a telemetry unit 46 that is part of or communicates with an external controller 60.

[0157] According to further embodiments, additional systems and devices suitable for implementing the methods presented herein are described in U.S. Patent No. 9,370,662 to Mika et al., issued June 21, 2016, and reference is made, for example, to FIGS. 9 and 14 of that patent. The entirety of U.S. Patent No. 9,370,662 is incorporated herein by reference.

[0158] In an embodiment, the controller 42 and / or the controller 60 may be operated according to any of the embodiments of the methods described herein.

[0159] The stimulation therapy customization and optimization method may be implemented using only the stimulation device 41 without using the external controller 60. In that case, the stimulation device 41 may be pre-programmed to implement a method such as method 100 of FIG. 1. When the stimulation device 41 is an implantable medical device such as a pacemaker-type device, the device 41 may be configured to implement the steps of method 100 except for the optional step 108 of presenting the measurement results, which may be omitted, or it may be achieved by the device 41 communicating a signal to an external display device such as the external controller 60 to display the results.

[0160] In other embodiments, the stimulation therapy customization method may be implemented using both the stimulation device 41 and the external controller 60. In such embodiments, the steps of method 100 may be common between the device 41 and the external controller 60. The stimulation device 41 may be configured to implement steps including the application of the stimulation pattern, and the external controller 60 may be configured to implement the remaining steps or a portion of the individual steps.

[0161] In another aspect, the present disclosure provides a non-transitory computer-readable medium storing software that may include instructions executable by one or more computers, such that upon such execution, the one or more computers may execute any of the methods described herein.

[0162] Generally, each of the device 41, the external controller 60, and the blood pressure measurement device 62 may be configured to be carried, transported, worn, or implanted in a person, and may include any computing device that wirelessly communicates with one or more networks. In particular, the external controller 60 and / or the blood pressure measurement device 62 may include a smartphone, such as a smartphone that executes an iPhone (registered trademark) or Android (trademark) operating system, or a smartwatch used in conjunction with such smartphones. The external controller 60 and / or the blood pressure measurement device 62 may broadly include any mobile device that includes a processor, a machine-readable medium that may include electronic instructions executed by the processor, and wireless networking hardware that enables the mobile device to communicate with other computing devices via a wireless network. In an embodiment, the external controller 60 and / or the blood pressure measurement device 62 may be a mobile personal computer (e.g., a laptop), a tablet computer, or even a desktop computer.

[0163] In an embodiment, the external controller 60 may generally be any computing device including a processor and a machine-readable medium containing instructions that may be executed by the processor. Generally, the processes and methods of the embodiments described in this detailed description and shown in the drawings can be implemented using any type of computing system having one or more central processing units (CPUs) and / or graphics processing units (GPUs). The processes and methods of the embodiments can also be implemented using application-specific electronic circuits such as application-specific integrated circuits (ASICs). The processes and methods of the embodiments can also be implemented using a computing system including read-only memory (ROM) and / or random access memory (RAM) that may be connected to one or more processing devices. Embodiments of computing systems and devices include, but are not limited to, servers, mobile phones, smartphones, tablet computers, notebook computers, laptops or desktop computers, and all-in-one computers.

[0164] The processes and methods of the embodiments can be stored as instructions and / or data on a non-transitory computer-readable medium. The non-transitory computer-readable medium may include any suitable computer-readable medium, such as a memory like RAM, ROM, flash memory, or any other type of memory known in the art. In some embodiments, the non-transitory computer-readable medium may include, for example, an electronic storage device, a magnetic storage device, an optical recording device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of such devices. More specific examples of non-transitory computer-readable media may include a portable computer diskette, a floppy disk, a hard disk, a magnetic disk or tape, a read-only memory (ROM), a random access memory (RAM), a static random access memory (SRAM), a portable compact disk read-only memory (CD-ROM), an erasable programmable read-only memory (EPROM or flash memory), an electrically erasable programmable read-only memory (EEPROM), a digital versatile disk (DVD and DVD-ROM), a memory stick, other types of solid state drives, and any suitable combination of these exemplary media. As used herein, a non-transitory computer-readable medium should not be construed to be a transient signal such as a radio wave or other freely propagating electromagnetic wave, an electromagnetic wave propagating through a waveguide or other transmission medium (e.g., an optical pulse passing through an optical fiber cable), or an electrical signal transmitted through a wire.

[0165] The instructions stored on a non-transitory computer-readable medium to implement the operation of the present embodiment may be instruction set architecture (ISA) instructions, assembler instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, configuration data for integrated circuits, state setting data, or source code or object code written in any one of one or more programming languages including object-oriented programming languages such as Smalltalk, C++, or a suitable language, and procedural programming languages such as the "C" programming language or a similar programming language.

[0166] In one or more embodiments, the described functions may be implemented by hardware, software, firmware, or any combination thereof. When implemented by software or firmware, the functions may be stored as one or more instructions or codes on a computer-readable medium and executed by a hardware-based processing unit. The computer-readable medium may include a computer-readable storage medium corresponding to a tangible medium such as a data storage medium (e.g., RAM, ROM, EEPROM, flash memory, or any other medium that can be used to store the desired program code in the form of instructions or data structures and can be accessed by a computer). The instructions may be executed by one or more processors such as one or more digital signal processors (DSPs), general-purpose microprocessors, application-specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated circuits or discrete logic electronic circuits. Thus, as used herein, the term "processor" may be any of the foregoing structures or any other structure suitable for implementing the embodiments of the technology described herein. Also, the present technology may be fully implemented by one or more circuits or logic elements.

[0167] According to the present embodiment, the following items are presented: Item 1: A system for customizing a blood pressure lowering stimulation therapy for a patient, comprising at least one controller, a stimulation device configured to generate a control signal related to the patient's heart, and a control circuit configured to send the control signal to the patient's heart, wherein the at least one controller is configured to apply a predetermined stimulation pattern to determine whether the specified criteria are met by the predetermined stimulation pattern, and if the specified criteria are not met by the predetermined stimulation pattern, calculate and apply a new stimulation pattern to determine whether the specified criteria are met by the new stimulation pattern.

[0168] Item 2: In the system of Item 1, the at least one controller may be external to the stimulation device.

[0169] Item 3: In the system according to any one of Items 1 and 2, the system may further comprise a blood pressure measuring device configured to provide blood pressure data to the at least one controller.

[0170] Item 4: In the system according to any one of Items 1 to 3, the at least one controller is configured to calculate one or more parameters including an average systolic measurement value, a slope, an individual error, and / or an average error when determining whether the specified criteria are met by any predetermined stimulation pattern and when determining whether the specified criteria are met by any new stimulation pattern, and compare each calculated parameter among the one or more calculated parameters with an allowable range of values of each calculated parameter.

[0171] Item 5: In the system according to any one of Items 1 to 4, when determining whether any predetermined stimulation pattern satisfies a specified determination criterion and when determining whether any new stimulation pattern satisfies the specified determination criterion, at least one controller calculates a weighted score of the stimulation pattern by multiplying each of one or more parameters by a weighting factor of a predetermined parameter, and may be configured to compare the calculated weighted score of the stimulation pattern with the weighted scores of other stimulation patterns and / or a predetermined required minimum weighted score.

[0172] Item 6: In the system of Item 4, the slope, individual errors, and average error may be calculated by linear approximation.

[0173] Item 7: In the system according to any one of Items 4 and 6, the average systolic measurement value may be calculated using only a short atrioventricular delay sublist of systolic blood pressure values.

[0174] Item 8: In the system according to any one of Items 1 to 7, at least one controller may be configured to determine a patient's baseline blood pressure parameter, determine an optimal stimulation pattern for the patient from among the applied predetermined stimulation pattern and the applied new stimulation pattern, and apply the optimal stimulation pattern for the patient.

[0175] Item 9: In the system of Item 8, the baseline blood pressure parameter may include at least one of the average systolic measurement value, the approximate slope, individual errors, or the average error.

[0176] Item 10: In the system according to any one of Items 8 and 9, at least one controller is configured to measure the baseline blood pressure before stimulation during a period before applying the first stimulation pattern and before being activated, apply the first stimulation pattern, measure the baseline blood pressure after the first stimulation during a period after applying the first stimulation pattern and before being activated, and determine the first baseline blood pressure of the patient based on the measured baseline blood pressure before stimulation and the measured baseline blood pressure after the first stimulation, and may be configured to determine the baseline blood pressure parameter of the patient. The first baseline blood pressure is used to determine the effect of the first stimulation pattern on the first blood pressure, and the effect on the first blood pressure may be used to determine whether the first stimulation pattern meets the specified criteria.

[0177] Item 11: In the system of Item 10, determining the first baseline blood pressure of the patient may include calculating the average of the measured baseline blood pressure before stimulation and the measured baseline blood pressure after the first stimulation.

[0178] Item 12: In the system according to any one of Items 10 and 11, at least one controller is further configured to apply the second stimulation pattern, measure the baseline blood pressure after the second stimulation during a period after applying the second stimulation pattern and before being activated, and determine the second baseline blood pressure of the patient based on the measured baseline blood pressure after the first stimulation and the measured baseline blood pressure after the second stimulation, and may be configured to determine the baseline blood pressure parameter of the patient. The second baseline blood pressure is used to determine the effect of the second stimulation pattern on the second blood pressure, and the effect on the second blood pressure may be used to determine whether the second stimulation pattern meets the specified criteria.

[0179] Item 13: In the system according to any one of Items 1 to 12, each of the predetermined stimulation patterns may include a periodic stimulation pattern consisting of a plurality of beats with a shorter atrioventricular delay and, subsequently, a plurality of beats with a longer atrioventricular delay. At least one controller is configured to identify a stimulation pattern that provides the best effect from among the previously applied predetermined stimulation patterns, determine whether the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, and if the predetermined stimulation pattern that provides the best effect has an acceptable level of stability, decrease the shorter atrioventricular delay of the predetermined stimulation pattern that provides the best effect by an increment and determine whether a stimulation pattern with the decreased shorter atrioventricular delay has been applied. If a stimulation pattern with the decreased shorter atrioventricular delay has not been applied, designate, as a new stimulation pattern to be applied to the patient, a stimulation pattern with the decreased shorter atrioventricular delay. If a stimulation pattern with the decreased shorter atrioventricular delay has been applied, reduce the number of beats with the shorter atrioventricular delay of the stimulation pattern with the decreased shorter atrioventricular delay, provide a stimulation pattern with the decreased shorter atrioventricular delay with the beats reduced, and designate, as a new stimulation pattern to be applied to the patient, the stimulation pattern with the decreased shorter atrioventricular delay with the beats reduced, so as to calculate a new stimulation pattern.

[0180] Item 14: In the system of Item 13, at least one controller is further configured to, when a predetermined stimulation pattern that provides the best effect does not have an acceptable level of stability, increase the longer atrioventricular delay of the predetermined stimulation pattern that provides the best effect by an increment, determine whether a stimulation pattern with the increased longer atrioventricular delay has been applied, and if a stimulation pattern with the increased longer atrioventricular delay has not been applied, designate a stimulation pattern with the increased longer atrioventricular delay as a new stimulation pattern to be applied to the patient, and if a stimulation pattern with the increased longer atrioventricular delay has been applied, decrease the shorter atrioventricular delay of the stimulation pattern with the increased longer atrioventricular delay by an increment, provide a decreased shorter atrioventricular delay stimulation pattern, and designate the decreased shorter atrioventricular delay stimulation pattern as a new stimulation pattern to be applied to the patient, so as to calculate a new stimulation pattern.

[0181] Item 15: In the system according to any one of Items 1 to 14, at least one controller may be configured to limit the application of a predetermined stimulation pattern and the application of a new stimulation pattern within a time allocated based on the patient's needs.

[0182] Item 16: In the system according to any one of Items 1 to 15, at least one controller may be configured to determine an inspection protocol based on the patient's baseline blood pressure parameters.

[0183] Item 17: In the system of Item 16, the inspection protocol may include at least one of the total time for completing the customization of the patient's blood pressure lowering stimulation therapy, a specific predetermined stimulation pattern for the patient, the number and / or time of the predetermined stimulation pattern applied to the patient, or the number and / or time of the new stimulation pattern applied to the patient.

[0184] Item 18: In the system according to any one of Items 1 to 17, the specified determination criterion may include at least one of slope and error.

[0185] Item 19: In the system according to any one of Items 1 to 18, the specified determination criterion may include at least one of a blood pressure stop condition, a lower limit of blood pressure drop, or a noise limit of measurement results.

[0186] Item 20: In the system according to any one of Items 1 to 19, at least one controller may be configured to calculate a new stimulation pattern by obtaining systolic blood pressure values and diastolic blood pressure values 0 to 300 seconds before stimulation, during stimulation, and 0 to 300 seconds after stimulation.

[0187] Item 21: In the system according to any one of Items 1 to 20, at least one controller may be configured to calculate a new stimulation pattern by calculating parameters within a period and between periods.

[0188] The foregoing disclosure has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the embodiments to the exact forms disclosed. Many modifications and variations of the embodiments described herein will be apparent to those skilled in the art in light of the above disclosure.

[0189] Although various embodiments have been described, the description is intended by way of illustration and not limitation, and it will be apparent to those skilled in the art that many more embodiments and aspects within the scope of those embodiments are possible. Any feature of any embodiment may be used in combination with any other feature or element in any other embodiment, or may be used in place of any other feature or element, unless otherwise particularly limited. Accordingly, the embodiments are not limited except as viewed in light of the appended claims and their equivalents. Also, within the scope of the appended claims, various modifications and changes are possible.

[0190] Furthermore, when describing exemplary embodiments, this specification may present methods and / or processes as a particular order of steps. However, to the extent that a method or process does not depend on the particular order of steps described herein, the method or process should not be limited to the particular order of steps described. As will be understood by those skilled in the art, other orders of steps are possible. Accordingly, the particular order of steps described herein should not be construed as a limitation of the claims. In addition, the claims regarding methods and / or processes should not be limited to performing those steps in the written order, and those skilled in the art can readily understand that changing the order still remains within the spirit and scope of this embodiment.

Claims

1. At least one controller, A stimulator configured to generate control signals related to the patient's heart, A control circuit configured to send the control signal to the patient's heart and Equipped with, The aforementioned at least one controller is A predetermined stimulus pattern is applied to determine whether the predetermined stimulus pattern satisfies the specified criteria. If the predetermined stimulus pattern does not satisfy the specified criteria, a new stimulus pattern is calculated and applied to determine whether the new stimulus pattern satisfies the specified criteria. A system configured to apply blood pressure lowering stimulation therapy to a patient.

2. The system according to claim 1, wherein the at least one controller is located outside the stimulator.

3. The system according to claim 1 or 2, further comprising a blood pressure measuring device configured to provide blood pressure data to at least one controller.

4. The at least one controller, when determining whether an arbitrary predetermined stimulus pattern satisfies the specified criteria, and when determining whether an arbitrary new stimulus pattern satisfies the specified criteria, Calculate one or more parameters, including the mean systolic measurement, slope, individual errors, and / or mean error. The calculated parameter from the one or more calculated parameters is compared with the acceptable range of values ​​for each calculated parameter. The system according to claim 1, configured as described above.

5. The at least one controller, when determining whether an arbitrary predetermined stimulus pattern satisfies the specified criteria, and when determining whether an arbitrary new stimulus pattern satisfies the specified criteria, A weighting score for the stimulus pattern is calculated by multiplying each of the one or more parameters by a predetermined parameter weighting coefficient. The calculated weighting score for the stimulus pattern is compared with the weighting scores of other stimulus patterns and / or a predetermined minimum required weighting score. The system according to claim 1, configured as described above.

6. The system according to claim 4, wherein the slope, the individual errors, and the average error are calculated by linear approximation.

7. The system according to claim 4 or 6, wherein the mean systolic measurement is calculated using only the short atrioventricular delay sublist of systolic blood pressure values.

8. The aforementioned at least one controller is Determine the baseline blood pressure parameters of the aforementioned patients. From the predetermined stimulation patterns applied and the newly applied stimulation patterns, the optimal stimulation pattern for the patient is determined. The optimal stimulation pattern is applied to the patient. The system according to claim 1, configured as described above.

9. The system according to claim 8, wherein the baseline blood pressure parameters include at least one of the mean systolic measurement, approximate slope, individual error, or mean error.

10. The aforementioned at least one controller is Before applying the first stimulation pattern and during the non-activation period, measure the baseline blood pressure before stimulation. Applying the first stimulation pattern, After applying the first stimulation pattern and during the non-activation period, the baseline blood pressure after the first stimulation is measured. The first baseline blood pressure of the patient is determined based on the measured baseline blood pressure before stimulation and the measured baseline blood pressure after the first stimulation. The system is configured to determine the baseline blood pressure parameters of the patient, The first baseline blood pressure is used to determine the effect of the first stimulation pattern on the first blood pressure. The first effect on blood pressure is used to determine whether the first stimulation pattern satisfies the specified criteria. The system according to claim 8 or claim 9.

11. The system according to claim 10, wherein determining the first baseline blood pressure of the patient comprises calculating the mean of the measured baseline blood pressure before stimulation and the measured baseline blood pressure after the first stimulation.

12. The aforementioned at least one controller further, Applying a second stimulus pattern, After applying the second stimulation pattern, and during the non-activation period, the baseline blood pressure after the second stimulation is measured. The second baseline blood pressure of the patient is determined based on the baseline blood pressure measured after the first stimulus and the baseline blood pressure measured after the second stimulus. The system is configured to determine the baseline blood pressure parameters of the patient, The second baseline blood pressure is used to determine the effect of the second stimulation pattern on the second blood pressure. The second effect on blood pressure is used to determine whether the second stimulation pattern satisfies the specified criteria. The system according to claim 10.

13. Each of the predetermined stimulation patterns includes a periodic stimulation pattern consisting of a plurality of beats with shorter atrioventricular delays, followed by a plurality of beats with longer atrioventricular delays. The aforementioned at least one controller is Identifying the stimulation pattern that produces the best effect from among a predetermined set of stimulation patterns that have been applied in advance, To determine whether the predetermined stimulation pattern that produces the best effect has an acceptable level of stability, If the predetermined stimulation pattern that produces the best effect has an acceptable level of stability, then the shorter atrioventricular delay of the predetermined stimulation pattern that produces the best effect is incrementally reduced, and it is determined whether the stimulation pattern with the reduced shorter atrioventricular delay was applied. If the aforementioned stimulation pattern having a reduced shorter atrioventricular delay is not applied, the aforementioned stimulation pattern having a reduced shorter atrioventricular delay is designated as a new stimulation pattern to be applied to the patient. If the aforementioned stimulation pattern having a reduced shorter atrioventricular delay was applied, the number of heartbeats having the reduced shorter atrioventricular delay in the aforementioned stimulation pattern having a reduced shorter atrioventricular delay is reduced, and a reduced shorter atrioventricular delay stimulation pattern with reduced heartbeats is provided, and the reduced shorter atrioventricular delay stimulation pattern with reduced heartbeats is designated as a new stimulation pattern to be applied to the patient. The system according to claim 1, configured to calculate a new stimulus pattern by

14. The aforementioned at least one controller further, If the predetermined stimulation pattern that produces the best effect does not have an acceptable level of stability, the longer atrioventricular delay of the predetermined stimulation pattern that produces the best effect is increased incrementally, and it is determined whether the stimulation pattern with the increased longer atrioventricular delay was applied. If the stimulation pattern having the increased and longer atrioventricular delay is not applied, the stimulation pattern having the increased and longer atrioventricular delay is specified as a new stimulation pattern to be applied to the patient. If the aforementioned stimulation pattern having an increased, longer atrioventricular delay was applied, the aforementioned shorter atrioventricular delay of the aforementioned stimulation pattern having an increased, longer atrioventricular delay is incrementally reduced to provide a reduced, shorter atrioventricular delay stimulation pattern, and the reduced, shorter atrioventricular delay stimulation pattern is designated as a new stimulation pattern to be applied to the patient. The system according to claim 13, configured to calculate a new stimulus pattern by

15. The system according to claim 1, wherein the at least one controller is configured to limit the application of the predetermined stimulation pattern and the application of the new stimulation pattern to a time allocated based on the patient's needs.

16. The system according to claim 1, wherein the at least one controller is configured to determine the examination protocol based on the patient's baseline blood pressure parameters.

17. The system according to claim 16, wherein the examination protocol comprises at least one of the following: the total time to complete the application of the blood pressure lowering stimulation therapy to the patient; a specific predetermined stimulation pattern for the patient; the number or duration of the predetermined stimulation pattern applied to the patient; or the number or duration of the new stimulation pattern applied to the patient.

18. The system according to claim 1, wherein the specified judgment criterion includes at least one of slope and error.

19. The system according to claim 1, wherein the specified judgment criterion includes at least one of a blood pressure cessation condition, a blood pressure reduction limit, or a noise limit for the measurement result.

20. The system according to claim 1, wherein at least one controller is configured to calculate a new stimulation pattern by obtaining systolic and diastolic blood pressure values ​​for 0 to 300 seconds before stimulation, during stimulation, and 0 to 300 seconds after stimulation.

21. The system according to claim 1, wherein the at least one controller is configured to calculate a new stimulation pattern by calculating intraperiod and interperiod parameters.

22. To determine the baseline blood pressure parameters of the patient, Applying a predetermined stimulus pattern to determine whether the predetermined stimulus pattern satisfies the specified criteria, If the predetermined stimulus pattern does not satisfy the specified criteria, a new stimulus pattern is calculated and applied to determine whether the new stimulus pattern satisfies the specified criteria. The process involves determining the optimal stimulation pattern for the patient from among the previously applied predetermined stimulation patterns and the newly applied stimulation patterns. Applying the aforementioned optimal stimulation pattern to the patient, A method for applying blood pressure-lowering stimulation therapy to a patient, including the application of such therapy.

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