Implantable drug delivery system responsive to intra-cardiac pressure

The invention is directed to techniques for monitoring the condition of a patient, such as a patient having congestive heart failure, and appropriately modifying the patient's drug therapy as a function of a pressure in the patient's heart, such as the estimated pulmonary artery diastolic pressure. The drugs may be administered by an implanted drug delivery device. The drug selection, the drug dosage or both may be controlled as a function of the pressure and/or the activity level of the patient.

FIELD OF THE INVENTION

The present invention relates generally to the treatment of congestive heart failure with drugs that increase cardiac output, and more particularly to the treatment of congestive heart failure with an implanted drug delivery device.

BACKGROUND

Heart failure refers to the heart's inability to keep up with the demands made upon it. Congestive heart failure refers to an inability of the heart to pump an adequate amount of blood to the body tissues. Because the heart is unable to pump an adequate amount of blood, blood returning to the heart becomes congested in the venous and pulmonary system.

In a healthy heart, the heart pumps all of the blood that returns to it, according to the Frank-Starling law. Increased venous return leads to increased end diastolic volume, which causes increased strength of contraction and increased stroke volume. In addition to intrinsic control according to the Frank-Starling law, a healthy heart is subject to extrinsic control, such as stimulation by the sympathetic nervous system to enhance contractility.

In a patient experiencing congestive heart failure, intrinsic and extrinsic control mechanisms may not function properly, and consequently the heart may fail to pump an adequate amount of blood. A condition known as cardiac decompensation is used to describe heart failure that results in a failure of adequate circulation.

Failure of the left side of the heart is generally more serious than the failure of the right side. On the left side of the heart, blood returns from the pulmonary system and is pumped to the rest of the body. When the left side of the heart fails, there are consequences to both the pulmonary system and to the rest of the body. A patient with congestive heart failure may be unable to pump enough blood forward to provide an adequate flow of blood to his kidneys, for example, causing him to retain excess water and salt. His heart may also be unable to handle the blood returning from his pulmonary system, resulting in a damming of the blood in the lungs and increasing his risk of developing pulmonary edema.

Causing more blood to be expelled from the heart, i.e., increasing cardiac output would increase the blood flow to the organs and tissues and reduce the risk of damming of blood in the lungs caused by heart failure. Patients with congestive heart failure are often treated with drug therapy intended to increase their cardiac output. Drugs administered to treat congestive heart failure by increasing cardiac output often have a positive inotropic effect on the heart. Drugs that have a positive inotropic effect on the heart increase cardiac output by increasing the contractility of the heart, which causes the heart to beat more forcefully, which in turn causes the ventricles of the heart to eject more blood per stroke. Drugs that have a positive inotropic effect on the heart include cardiac glycosides such as digitalis, digoxin and digitoxin, beta-adrenergic agonists such as dopamine and dobutamine, and phosphodiesterase inhibitors such as amrinone and milrinone.

Often, a physician determines a course of drug therapy for a patient with congestive heart failure based on the patient's condition during an admission or office visit. The drugs to be administered and the dosages for those drugs are chosen at that time. The drugs may then be self-administered or administered via an implanted drug delivery device. In some cases, congestive heart failure patients frequently visit the physician's office to have their condition evaluated. At these visits, the patient may receive a supplemental drug or dosage or otherwise have the drug therapy modified as indicated by his condition. This situation may be very costly because of the hospital stay, nursing costs, patient transportation costs, and so forth.

Further, frequent visits fail to recognize changes in the patient's condition between visits. These changes may indicate an increased or decreased need for drug therapy that increases cardiac output. Because these changes are not recognized, the drug therapy is not modified to address them. If the changes indicate a worsening of the patient's condition and a need for increased cardiac output, failure to address them promptly may endanger the patient.

Therefore, there is a need for a system and method to monitor a congestive heart failure patient's condition, and appropriately modify the patient's drug therapy as a function of the patient's condition, in an outpatient setting.

Some existing methods monitor a patient's condition with an implanted physiological sensor, and control the operation of an implanted drug delivery device as a function of the patient's condition as measured by the physiological sensor. For example, U.S. Pat. No. 4,003,379, issue to Ellinwood, Jr., discloses controlling an implanted drug delivery device to deliver hypertension medication in response to blood pressure as measured by a pressure transducer implanted in the neck or lower extremities.

Some existing methods for monitoring a patient's condition in an outpatient situation use an implanted pressure monitor and sensor to estimate the patient's pulmonary artery diastolic pressure as a function of the blood pressure in the patient's right ventricle. For example, U.S. Pat. No. 5,368,040, issued to Carney, discloses a system that includes an implanted pressure monitor that can estimate the pulmonary artery diastolic pressure from a pressure signal received from a pressure sensor in the right ventricle. Further, U.S. Pat. No. 6,155,267, to Nelson, discloses using the occurrence of a change in the state of a physiological parameter, such as estimated pulmonary artery diastolic pressure, as a trigger to change the dosage of a drug delivered by an implanted drug delivery device.

None of the existing methods, however, disclose a system and method to monitor a congestive heart failure patient's condition and appropriately modify the patient's drug therapy as a function of the patient's condition in an outpatient situation. None of the existing methods disclose how to relate a measured intra-cardiac pressure, such as the estimated pulmonary artery diastolic pressure, to the congestive heart failure patient's need for increased cardiac output. Further, none of these methods disclose how to modify the drug therapy as a function of the measured pressure to meet this need.

Examples of the above referenced existing techniques and/or devices may be found in the issued U.S. Patents listed in Table 1 below.

All patents listed in Table 1 above are hereby incorporated by reference herein in their respective entireties. As those of ordinary skill in the art will appreciate readily upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments and claims set forth below, many of the devices and methods disclosed in the patents of Table 1 may be modified advantageously by using the techniques of the present invention.

SUMMARY OF THE INVENTION

The present invention has certain objects. That is, various embodiments of the present invention provide solutions to one or more problems existing in the prior art with respect to treatment of congestive heart failure patients with drugs that increase cardiac output. Such problems may include, for example, the inability to monitor a congestive heart failure patient's condition, and appropriately modify the patient's drug therapy as a function of the patient's condition, in an outpatient situation. It is an object of the present invention to provide a system and method to monitor a congestive heart failure patient's condition, and appropriately modify the patient's drug therapy as a function of the patient's condition, in an outpatient situation. In particular, it is an object of the present invention to monitor a congestive heart failure patient's estimated pulmonary artery diastolic pressure and modify the patient's drug therapy as a function of the estimated pulmonary artery diastolic pressure by, for example, selecting drugs and/or adjusting dosages of drugs as a function of the estimated pulmonary artery diastolic pressure.

The present invention has certain features. In particular, various embodiments of the present invention may include a drug delivery device capable of delivering one or more drugs that increase cardiac output, at a variety of different dosages. The drug delivery device may be an implantable drug pump. Various embodiments of the present invention may also include a processor that controls the function of the drug delivery device to, for example, control which of the plurality of drugs contained within the drug delivery device are delivered and/or at what dosage the drugs are delivered.

Various embodiments of the present invention may also include a pressure sensor that detects pressure within the heart, and a pressure monitor that receives a pressure signal from the pressure sensor. In some embodiments of the invention, the pressure monitor processes the pressure signal and measures a pressure value that is generally indicative of a congestive heart failure patient's condition, and is particularly indicative of a need for increased cardiac output. Further, in some embodiments, the pressure monitor may identify a point of maximum slope on a pressure signal to, for example, estimate the pressure in the right ventricle that causes the pulmonary valve to open. In some embodiments, the measured pressure value is then used to cause the drug delivery device to adjust the drug therapy delivered by the drug delivery device by, for example, causing the drug delivery device to deliver one or more different or additional drugs and/or adjusting the dosages of the drugs delivered.

Therefore, in various embodiments of the invention, the processor that controls the operation of the drug delivery device may receive a signal that indicates the measured pressure value from the pressure monitor. In various embodiments of the invention, the processor will generate a control signal in response to the measured pressure value, to control the drug delivery device to deliver one or more different or additional drugs and/or adjust the dosages of the drugs. In some embodiments the processor may select one or more drugs or dosage levels by comparing the measured pressure value to a look-up table of pressure values and associated drugs and dosage levels. In other embodiments, the processor might select the dosages by applying one or more equations that relate pressure values to dosage. The look-up table and/or equations may be stored in memory. The look-up table and/or equations may, for example, be received via remote distribution link or RF telemetry.

In various embodiments of the invention, the processor may also receive one or more signals that indicate the patient's activity level. In various embodiments of the invention, the processor will generate the control signal in response to the measured pressure value and the patient's activity level. In some embodiments, the patient's activity level may be compared to a threshold to determine whether, considering the measured pressure value and the patient's activity, the drug therapy should be adjusted. In other embodiments, the look-up table and/or equations will relate pressure values and activity levels to dosages and/or drugs.

In some embodiments, the processor may receive programming from a physician via remote distribution link or RF telemetry. In this manner, the patient's physician may customize the drug therapy for the patient. The patient's physician may specify, for example, suitable drugs and/or dosages for particular pressures, or for pressures and activity levels. The present invention presents techniques whereby the patient's physician can relate the patient's drug therapy to the monitored pressures.

In various embodiments of the present invention, the pressure monitor and processor cooperate to continuously monitor a pressure in a patient's heart that is indicative of the patient's need for increased cardiac output, and to adjust the patient's drug therapy to meet the increased need.

The present invention has certain advantages. That is, in comparison to known implementations for treatment of congestive heart failure patients with drugs that increase cardiac output, various embodiments of the present invention may provide one or more advantages. Such advantages may include, for example, the ability to monitor a congestive heart failure patient's condition, and appropriately modify the patient's drug therapy as a function of the patient's condition, in an outpatient situation.

For example, the system and method of the present invention may use an implanted pressure monitor to monitor a congestive heart failure patient's condition, and an implanted drug delivery device to deliver the patient's drug therapy, in an outpatient situation. The system and method of the present invention can continuously determine whether there is a need for increased cardiac output by processing a pressure signal that represents pressure in the heart to measure a pressure value indicative of whether increase cardiac output is needed. Consequently, costly office visits are avoided and changes in the patient's condition between office visits are addressed. Further, by more directly measuring the symptoms of cardiac decompensation as reflected in the pressure value, the present invention more effectively treats the condition with drug therapy by increasing cardiac output. Also, the system and method of the present invention effectively increase the cardiac output as needed by selecting the appropriate drugs and/or increasing the dosage of drugs as needed.

The above summary of the present invention is not intended to describe each embodiment or every embodiment of the present invention or each and every feature of the invention. Advantages and attainments, together with a more complete understanding of the invention, will become apparent and appreciated by referring to the following detailed description and claims taken in conjunction with the accompanying drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1shows a system10illustrating an embodiment of the invention in which estimated pulmonary artery diastolic pressure is used to select drugs and/or adjust the dosage of drugs to be delivered by a drug delivery device. System10, or any of its constituent components, could be implanted in a human being or an animal. System10includes drug delivery device12, which delivers drugs to a patient. Drug delivery device12may include one or more reservoirs. InFIG. 1, drug delivery device12is shown with two reservoirs14and16. Each reservoir14,16may contain a drug or a mixture of drugs. Drug delivery device12may further include one or more fill ports22and24that assist filling or refilling of reservoirs14and16.

Drug delivery device12may include one or more infusion apparatuses, such as catheters, that infuse drugs from reservoirs14,16to infusion sites within the patient's body.FIG. 1shows two catheters18and20. Catheter18is shown coupled to reservoir14and catheter20is shown coupled to reservoir16. In some embodiments of the present invention, each infusion apparatus may be coupled to more than one reservoir, or more than one infusion apparatus may be coupled to each reservoir. Drug delivery device12also may include one or more pumps (not shown) that deliver drugs from the reservoirs to the infusion apparatuses.

The infusion site may depend upon the drug being infused. Each of catheters18and20may dispense drugs at one or more infusion sites within the patient's body. For example, a catheter may deliver drugs to the patient's subclavian vein, superior vena cava, or to the patient's fatty tissue. If the patient has more than one catheter, the catheters need not deliver drugs to the same infusion site.

The drugs being delivered may be delivered by a constant drip, a periodic bolus, a combination of these methods, or some other delivery method. The present invention is not limited to a particular drug delivery method.

Drug delivery device12may be an implantable drug pump. Examples of implantable drug pumps include a number of SynchroMed™ pumps manufactured by and commercially available from Medtronic Inc. of Minneapolis, Minn. Pumps of this kind typically include self-sealing reservoirs that may be refilled by a needle and syringe, and need not be surgically removed when empty. The needle and syringe may also be used to drain a pump of one drug, flush the reservoir, and refilled the reservoir with a different drug. The invention is not limited to use with SynchroMed pumps, however, and may be adapted for use with other drug delivery devices.

System10also includes a processor26that controls the operation of drug delivery device12. By controlling the operation of drug delivery device12, processor26controls the drug therapy delivered to the patient at any given time. Processor26may, for example, control which drugs are delivered by the drug delivery device12, by controlling which pumps are active. Processor26may also control the dosage of the drugs delivered by drug delivery device12by controlling the activity of the pumps. Processor26may control the operation of drug delivery device12via control signal30.

The present invention presents techniques for selecting a drug therapy based on the pressure of the blood flowing inside the patient's heart. System10, as shown inFIG. 1, includes pressure monitor32, which is coupled to pressure sensor36by lead34. An example of pressure monitor32that may be used with this embodiment of the present invention is the Chronicle™ Implantable Hemodynamic Monitor manufactured by and commercially available from Medtronic, Inc. of Minneapolis, Minn. As will be described below, pressure monitor32may measure the estimated pulmonary artery diastolic pressure (ePAD) as a function of the pressure signals received from pressure sensor36.

Pressure sensor36responds to the absolute pressure inside the patient's heart. Pressure sensor36may be one of many forms of pressure sensors. One form of pressure sensor that is useful for measuring blood pressure inside a human heart is a capacitive absolute pressure sensor, as described in U.S. Pat. No. 5,564,434 to Halperin, et al., hereby incorporated by reference herein in its entirety. Pressure sensor36may also be a piezoelectric crystal or piezoresistive pressure transducer. The invention is not limited to any particular kind of pressure sensor.

Pressure monitor32is also coupled to electrode38located at the distal end of lead34near pressure sensor36. Electrode38senses the electrical activity in the heart. Pressure monitor32can sense R-waves via electrode38.

The pressure monitor32may also include an activity sensor46, which may be a piezoceramic accelerometer bonded to a hybrid circuit. Activity sensor46typically, although not necessarily, provides a sensor output that varies as a function of a measured parameter relating to the patient's metabolic requirements or activity level. Furthermore, pressure monitor32may calculate a heart rate as a function of R-R intervals collected via R-wave sensing. Based on the output of activity sensor46and/or the calculated heart rate, it may be determined if the patient is at rest, as indicated by minimal activity sensor output, or performing activities, as indicated by significant activity sensor output and elevated heart rates.

As shown inFIG. 1, processor26receives a signal40from pressure monitor32. Signal40may indicate the ePAD as measured by the pressure monitor32. Processor26may select a drug therapy as a function of signal40. Processor26may select one or more drugs from a plurality of drugs contained in drug delivery device12as a function of signal40, and may control the drug delivery device to deliver the selected drug or drugs. Processor26may select a dosage for one or more drugs delivered by drug delivery device12, and may control the drug delivery device12to deliver the each of the drugs at the selected dosage. In some embodiments of the present invention, processor26may perform both the drug selection function and the dosage selection function.

When signal40indicates an estimated pulmonary artery diastolic pressure value, processor26may select the drugs and/or dosages by comparing the ePAD value indicated by signal40to a look-up table of ePAD values and associated drugs and/or dosages. As an alternative, processor26may select the dosages for each of the one or more drugs to be delivered by applying equations that relate ePAD values to dosages. The look-up table or equations may be stored in memory28. The look-up table or equations may, for example, be received via remote distribution link42, RF telemetry44, or from an external programmer.

Processor26may also receive an activity sensor output47, which pressure monitor32generates from activity sensor46, and a signal48, which is indicative of the patient's heart rate, from pressure monitor32. Heart rate signal48may reflect R-waves sensed by pressure monitor32, in which case processor26may calculate the heart rate as a function of signal48. Alternatively, signal48may, if pressure monitor32itself calculates the heart rate from sensed R-waves, reflect the patient's heart rate. In either case, processor26determines the patient's activity level as a function of the activity sensor output47and/or the heart rate.

In such an embodiment, processor26may select one or more drugs to be delivered by drug delivery device12from a plurality of drugs contained in drug delivery device12as a function of pressure signal40and the determined activity level. In addition or in the alternative, processor26may select a dosage for one or more drugs to be delivered by drug delivery device12as a function of pressure signal40and the determined activity level. In some embodiments of the present invention, the activity level may be implemented as a threshold. For example, if the activity sensor output47and/or the heart rate exceed a threshold value, the processor may disregard an elevated ePAD and control drug delivery device12to deliver the same drugs at the same dosages. In other embodiments, processor26may select the drugs and/or dosages by comparing the ePAD value indicated by signal40, activity sensor output47, and the heart rate to a look-up table that maps ePAD values, activity sensor output values, and heart rate values to associated drugs and/or dosages. In an alternative embodiment, processor26may select the dosages for each of the one or more drugs to be delivered by applying equations that relate ePAD values, activity sensor output values, and heart rates to dosages. The threshold values, look-up table or equations may be stored in memory28. The threshold values, look-up table or equations may, for example, be received via remote distribution link42, RF telemetry44, or from an external programmer.

Although shown inFIG. 1as logically separate from pressure monitor32and drug delivery device12, processor26may be housed inside pressure monitor32, or inside drug delivery device12. Alternatively, processor26may be separate from both pressure monitor32and drug delivery device12. Further, pressure monitor32, drug delivery device12and processor26may be realized as a single implantable device.

Processor26may be implemented as a microprocessor, for example, or as an ASIC, FPGA, discrete logic circuitry, or analog circuitry. Processor26may execute instructions stored in memory28, which may comprise any computer-readable medium suitable for storing instructions, including random access memory (RAM), read-only memory (ROM) non-volatile random access memory (NVRAM), electrically erasable programmable read-only memory (EEPROM), flash memory, and the like.

FIG. 2is a diagram of a human heart50, including a pressure sensor36, electrode38and a lead34. Pressure sensor36and electrode38may, as shown inFIG. 2, be placed inside right ventricle54of heart50. Sensor36is coupled to lead34, which extends from right ventricle54, through right atrioventricular valve60, and through superior vena cava68. Lead34extends further through the patient's circulatory system, eventually exiting the circulatory system and coupling to implanted pressure monitor32(not shown inFIG. 2). Pressure monitor32may, for example, be implanted in the patient's abdomen or upper chest.

Sensor36may generate pressure signals itself or may modulate pressure signals conducted through lead34along wires76and78. The pressure signals are a function of the fluid pressure in right ventricle54. Pressure monitor32receives, monitors and analyzes the pressure signals, as will be described in more detail below.

In systole, right ventricle54and left ventricle58contract. For a brief period, no blood leaves ventricles54and58, and the contraction is isovolumetric. During isovolumetric contraction, right atrioventricular valve60and left atrioventricular valve64are closed by backward pressure differential forces. Aortic valve66and pulmonary valve62are likewise closed, as the pressure in ventricles54and58is insufficient to force blood through them.

Consequently, isovolumetric contraction causes the blood in ventricles54and58to undergo increasing pressure. In a short time, the pressure in right ventricle54overcomes the pressure in pulmonary arteries70and72, drives pulmonary valve62open, and ejects blood from right ventricle54into pulmonary arteries70and72. Similarly, the pressure in left ventricle58overcomes the pressure in aorta74, driving open aortic valve66and ejecting blood into aorta74. The pressure needed to open aortic valve66is normally much higher than the pressure needed to open pulmonary valve62.

The pressure needed to open pulmonary valve62is, for practical purposes, an accurate measure of the pulmonary artery diastolic pressure (PAD), and is referred to as the estimated pulmonary artery diastolic pressure or ePAD. ePAD is a significant pressure in patient monitoring. In particular, ePAD reflects the condition of a congestive heart failure patient.

ePAD is a significant pressure because ePAD closely reflects the pulmonary capillary wedge pressure, or PCWP, which reflects the average pressure in left atrium56over a cardiac cycle, also called the mean left atrial pressure or mean LAP. In addition, ePAD reflects the filling pressure in left ventricle58during diastole, also called the left ventricular end diastolic pressure or LVEDP. In a healthy heart, LAP and LVEDP range from approximately 8 mmHg to 12 mmHg. ePAD may be somewhat higher than LAP and LVEDP, but past studies indicate a strong correlation between ePAD, PCWP, mean LAP and LVEDP. In a heart having congestive heart failure, each of these pressures may be considerably elevated, as will be discussed below.

Mean LAP and LVEDP are pressures on the left side of heart50. Practical considerations make it difficult to measure pressures on the left side of heart50directly. These pressures may be measured indirectly, however, by placing sensor36in right ventricle54and measuring ePAD with pressure monitor32.

Measurement of ePAD is not equivalent to measuring the highest pressure in right ventricle54. During isovolumetric contraction in systole, the pressure in right ventricle54increases and forces pulmonary valve62open. Pressure in right ventricle54does not peak at this point, however. Rather, pressure in right ventricle54increases during ejection as well, but the pressure increases at a reduced rate.

It is this change in the rate of increase of pressure that helps identify ePAD, as illustrated inFIG. 3. Pressure signal80from sensor36in right ventricle54is shown in reference to ventricular electrogram (EGM) signal82. EGM signal82may be sensed by electrode38.

R-wave84in EGM signal82represents ventricular depolarization of heart50. Following ventricular depolarization, pressure in right ventricle54increases, eventually reaching a peak pressure at86.

When the pressure in right ventricle54overcomes the pressure in pulmonary arteries70and72, pulmonary valve62is driven open. When pulmonary valve62opens, contraction is no longer isovolumetric. Pressure in right ventricle54, although still increasing due to ventricular contraction, increases at a slower rate. As a result, there is an inflection point88in pressure signal80when pulmonary valve62opens.

ePAD may be found by determining the pressure at the point on right ventricular pressure curve80corresponding to the inflection point88. Inflection point88may be found by taking the first derivative of right ventricular pressure with respect to time, or dP/dt. Because the slope of pressure signal80is at its maximum at inflection point88, the peak92of dP/dt signal90corresponds to inflection point88. Therefore, ePAD may be found by finding the point on right ventricular pressure signal80corresponding to the maximum value of dP/dt. Inflection point88may also be found by taking the second derivative of right ventricular pressure with respect to time, or d2P/dt2. In this case, ePAD is the pressure at the point on right ventricular pressure signal80corresponding to the point96at which signal94of d2P/dt2goes negative for the first time after R-wave84. The time at which inflection point88, peak92and zero crossing96occur is indicated by reference line98.

Pressure monitor32may include differentiating circuits that generate d2P/dt2signal94and/or dP/dt signal90. Pressure monitor32may further include circuits to detect when d2P/dt2signal94crosses zero in the negative direction after the R-wave, or when dP/dt signal90peaks, both of which occur at time98. By detecting when inflection point88occurs, pressure monitor32may measure the pressure102in right ventricle54at inflection point88, which is ePAD.

FIG. 3also shows an exemplary pulmonary artery pressure curve100superimposed on right ventricle pressure signal80. As shown inFIG. 3, the point102at which pulmonary artery pressure is nearly equal to the right ventricle pressure is at inflection point88, when signal80and curve100cross each other. The pressure at inflection point88is ePAD, the pressure at which the pressure in right ventricle54overcomes the pressure in pulmonary arteries70and72, opening pulmonary valve62. It has been verified by experimentation that ePAD is a close estimation of PAD.

As mentioned above, patients having chronic congestive heart failure often exhibit elevated ePAD levels. This is because the hearts of patients having congestive heart failure may fail to achieve adequate circulation to their organs and tissues, a condition known as cardiac decompensation. As a result of the inability to achieve adequate forward circulation, the hearts of congestive heart failure patients may also fail to adequately expel the blood that is being returned to them from the organs and tissues. When blood is unable to return to the heart from the pulmonary system, the blood dams up in the lungs, and pulmonary edema results.

The damming of the blood in the lungs leads to increased pressure in the pulmonary circulatory system, which results in an elevated pulmonary artery pressure. Elevated pulmonary artery pressure is therefore an indication of the condition of a congestive heart failure patient, and a sign of risk of pulmonary edema.

Because ePAD is a close approximation of pulmonary artery pressure, elevated ePAD is also an indication of the congestive heart failure patient's condition, and a sign of risk of pulmonary edema. In general, as a patient's ePAD approaches approximately 25 mmHg, the patient's risk of pulmonary edema increases. When a patient's ePAD exceeds 25 mmHg, pulmonary edema is very likely to occur.

Cardiac decompensation and pulmonary edema can be serious. In many cases, the conditions require intensive care and hospitalization. Cardiac decompensation and pulmonary edema can be fatal.

Causing more blood to be expelled from the heart, i.e., increasing cardiac output would increase the inadequate forward flow of blood to the organs and reduce the damming of blood in the lungs caused by cardiac decompensation. Therefore, therapies to treat congestive heart failure patients may include therapies to increase cardiac output.

Cardiac output (CO) is defined as the volume of blood pumped by each ventricle per minute. CO is determined by two factors: heart rate (HR) in units of beats per minute, and stroke volume (SV) in units of volume of blood pumped per stroke, i.e., per beat. The relationship between CO, HR and SV is usually expressed:
CO=HR×SV

One way to increase CO is to increase SV, i.e., cause the ventricles to pump more blood per beat. One way to cause the ventricles to pump more blood per beat is administer a drug with a positive inotropic effect on the heart. A drug with a positive inotropic effect on the heart increases the heart's contractility, i.e. causes the heart to beat more forcefully, thereby ejecting more blood volume per stroke. Drugs that have a positive inotropic effect on the heart include cardiac glycosides such as digitalis, digoxin and digitoxin, beta-adrenergic agonists such as dopamine and dobutamine, and phosphodiesterase inhibitors such as amrinone and milrinone.

Because elevated ePAD reflects the damming of blood in the lungs, which is a symptom of congestive heart failure, ePAD may also reflect the need for increased cardiac output to overcome cardiac decompensation. Consequently, ePAD reflects the need for a therapy to increase the cardiac output. Thus, ePAD may, for example, reflect the need to change from one of the drugs listed above to another more potent drug or combination of drugs listed above. ePAD may also reflect the need to increase or decrease the dosage of one or more of the drugs listed above. The present invention is not limited to the listed drugs or classes of drugs, but is instead intended to include use of any drug to increase cardiac output.

Techniques for ePAD-based adjustment of the dosage of a drug that increases cardiac output are shown inFIG. 4. Pressure monitor32monitors pressure in the right ventricle54of the heart50via pressure sensor36coupled to lead34(110). Pressure monitor32also processes the pressure signal that it receives from pressure sensor36to measure the estimated pulmonary artery diastolic pressure (112). Pressure monitor32may, for example, identify the pressure value at the point of maximum slope in the pressure signal by either of the techniques described above. Pressure monitor32generates a pressure signal40as a function of the measured ePAD, which is received by processor26.

Processor26selects a dosage for each of the one or more drugs to be delivered by drug delivery device12as a function of pressure signal40(114) and generates control signal30, which is received by drug delivery device12. Drug delivery device12delivers each of the one or more drugs to the patient at the selected dosage as a function of control signal30(116) by, for example, increasing or decreasing the rate of one or more of its drug pumps. If pressure monitor32detects an elevated ePAD, for example, processor26may generate control signal30to cause drug delivery device12to increase the dosage of the one or more drugs that are delivered to the patient.

Increasing the dosage of the one or more drugs delivered by drug delivery device12may increase the cardiac output. The results of increasing the cardiac output may be reflected in the measured ePAD, which may be used to further adjust dosage of the drug delivered by drug delivery device12. Thus, system10may use feedback continually to monitor ePAD and adjust the dosage of one or more drugs delivered to the patient as a function of the ePAD (118).

FIG. 5is a graph illustrating an exemplary relationship between ePAD and dosage. Curve120defines the appropriate dosage as a function of the patient's calculated ePAD. Curve120may be defined by an equation that applies over a range of ePAD values, the equation being of the general form dosage=f(ePAD).

As shown inFIG. 5, the dosage increases non-linearly as the patient's ePAD approaches 25 mmHg (122). The increase in slope of curve120represents a rapid increase in dosage when the patient is at risk of pulmonary edema up to the maximum dosage124for the particular drug. The rapid increase causes SV to rise, consequently boosting CO, thereby alleviating the damming in the pulmonary circulation, reducing the pulmonary artery pressure, and reducing the risk of pulmonary edema. Although curve120defines dosages corresponding to an ePAD of about 14 mmHg or greater, the present invention contemplates the definition of dosages over any range of ePAD values.

The dosage is limited to the patient's safe maximum dosage124. Therefore, programming the device above a safe dosage limit is not possible. This maximum level is tailored to the patient and chosen by the physician.

The relationship between ePAD and dosage may also be described by discrete dosages for discrete ePAD values or ranges of ePAD values.FIG. 5shows one such correlation between discrete ePAD values and discrete dosages, resulting in a piecewise linear relationship126. The subset of ePAD values between 20 mmHg and 22 mmHg, for example, corresponds to a single dosage. Similarly, other subsets of ePAD values correspond to single dosages.

Techniques for ePAD-based selection of one or more drugs from a plurality of drugs that increase cardiac output are shown inFIG. 6. Pressure monitor32monitors pressure in the right ventricle54of the heart50via pressure sensor36coupled to lead34(130). Pressure monitor32also processes the pressure signal that it receives from pressure sensor36to measure the estimated pulmonary artery diastolic pressure (132). Pressure monitor32may, for example, identify the pressure value at the point of maximum slope in the pressure signal by either of the techniques described above. Pressure monitor32generates a pressure signal40as a function of the measured ePAD, which is received by processor26.

Processor26selects one or more drugs to be delivered by drug delivery device12from a plurality of drugs contained in drug delivery device12as a function of pressure signal40(134) and generates control signal30, which is received by drug delivery device12. Drug delivery device12delivers the one or more selected drugs to the patient as a function of control signal30(136) by, for example, activating the one or more drug pumps associated with the reservoirs that contain the selected drugs. For example, if the ePAD value measured by pressure monitor32and delivered to processor26via pressure signal40indicates that the drug contained in reservoir14should be delivered to the patient, processor26will select that drug and send control signal30to drug delivery device12to cause drug delivery device12to activate the pump associated with reservoir14.

Changing the delivered drug or delivering additional drugs may increase the cardiac output. The results of increasing the cardiac output may be reflected in the measured ePAD, which may be used to make further changes to the roster of drugs delivered by drug delivery device12. Thus, system10may use feedback continually to monitor ePAD and select the appropriate one or more drugs to be delivered to the patient as a function of the ePAD (138).

FIG. 7is a graph illustrating an exemplary relationship between ePAD and drug selection. Between 12 mmHg and 18 mmHg, drug140of a first effectiveness with respect to increasing cardiac output is delivered at a constant dosage. In this example, at 18 mmHg the need for increased cardiac output has exceeded the effectiveness of drug140. Delivery of drug140ceases in favor of delivery of drug142at a higher dosage, which has a higher effectiveness with respect to increasing cardiac output. As the patient's measured ePAD approaches 25 mmHg (144) and pulmonary edema is eminent, supplemental drug146is delivered in addition to drug142in a further effort to increase cardiac output.

A combined technique for ePAD-based adjustment to drug therapy, combining the techniques for ePAD-based selection of one or more drugs from a plurality of drugs and ePAD-based adjustment of the dosage of one or more drugs, is shown inFIG. 8. Pressure monitor32monitors pressure in the right ventricle54of the heart50via pressure sensor36coupled to lead34(150). Pressure monitor32also processes the pressure signal that it receives from pressure sensor36to measure the estimated pulmonary artery diastolic pressure (152). Pressure monitor32may, for example, identify the pressure value at the point of maximum slope in the pressure signal by either of the techniques described above. Pressure monitor32generates a pressure signal40as a function of the measured ePAD, which is received by processor26.

Processor26selects one or more drugs to be delivered by drug delivery device12from a plurality of drugs contained in drug delivery device12as a function of pressure signal40(154), selects a dosage for each of the one or more selected drugs as a function of pressure signal40(156), and generates control signal30, which is received by drug delivery device12. Drug delivery device12delivers each of the one or more selected drugs to the patient at the selected dosage as a function of control signal30(158) as described above. Furthermore, as described above the results of adjusting the drug therapy may be reflected in the measured ePAD, which may be used to further adjust the drug therapy. Thus, system10may use feedback continually to monitor ePAD and select drugs and adjust dosages as a function of the ePAD (160).

FIG. 9is a graph illustrating an exemplary relationship between ePAD and a drug therapy that includes three drug options170,172and174. The curve for each of the drugs170,172and174defines the appropriate dosage as a function of the patient's calculated ePAD. Each curve may be defined by an equation that applies over a range of ePAD values, the equation being of the general form dosage=f(ePAD). The relationship between ePAD and dosage for each of the drugs170,172and174may also be described by discrete dosages for discrete ePAD values or ranges of ePAD values as described with reference toFIG. 5.

As shown inFIG. 9, between 10 mmHg and 18 mmHg, drug170of a first effectiveness with respect to increasing cardiac output is delivered. Drug170is delivered in a linearly increasing fashion to meet the increased need for cardiac output evidenced by the increased measured ePAD values throughout this range. In this example, at 18 mmHg the need for increased cardiac output has exceeded the effectiveness of drug170. Delivery of drug170ceases in favor of delivery of drug172, which has a higher effectiveness with respect to increasing cardiac output. Between 18 mmHg and 23 mmHg, drug172is also delivered in a roughly linearly increasing fashion to meet the increased need for cardiac output. As the patient's measured ePAD approaches 25 mmHg (176) and pulmonary edema is eminent, the dosage of drug172increases non-linearly and supplemental drug174is delivered in addition to drug172in a further effort to increase cardiac output. The rapid increase in the dosage of drug172and the addition of supplemental drug174cause SV to rise, consequently boosting CO, thereby alleviating the damming in the pulmonary circulation, reducing the pulmonary artery pressure, and reducing the risk of pulmonary edema.

During periods of exercise, the ePAD can increase significantly as the loading conditions to the left side of the patient's heart increase. An increase in ePAD caused by the patient's increased activity might not indicate a change in the patient's condition or a need for increased cardiac output. Therefore it may be desirable to consider the patient's activity level in addition to the measured ePAD when determining whether to adjust the drug therapy.

A further technique for ePAD-based adjustment to drug therapy, combining the techniques described above with a consideration of the patient's activity level, is shown inFIG. 10. Pressure monitor32monitors pressure in the right ventricle54of the heart50via pressure sensor36coupled to lead34(180). Pressure monitor32also processes the pressure signal received from pressure sensor36to measure the estimated pulmonary artery diastolic pressure (182). Pressure monitor32may, for example, identify the pressure value at the point of maximum slope in the pressure signal by either of the techniques described above. Pressure monitor32generates a pressure signal40as a function of the measured ePAD, which is received by processor26.

Processor26also receives an activity sensor output47, which pressure monitor32generates from activity sensor46, and a signal48, which is indicative of the patient's heart rate, from pressure monitor32. Heart rate signal48may reflect R-waves sensed by pressure monitor32, in which case processor26may calculate the heart rate as a function of signal48. Alternatively, signal48may, if pressure monitor32itself calculates the heart rate from sensed R-waves, reflect the patient's heart rate. In either case, processor26determines the patient's activity level as a function of the activity sensor output47and/or the heart rate (184).

Processor26selects one or more drugs to be delivered by drug delivery device12from a plurality of drugs contained in drug delivery device12as a function of pressure signal40and the determined activity level (186), selects a dosage for each of the one or more selected drugs as a function of pressure signal40and the determined activity level (188), and generates control signal30, which is received by drug delivery device12. In some embodiments of the present invention, when processor26receives an elevated ePAD from pressure monitor32and also determines an increased activity level as a function of activity sensor output47and signal48, processor26may determine that no ePAD-based change to the drugs or dosages should be made. If, on the other hand, processor26receives an elevated ePAD in the absence of an increased activity level, processor26may select the drugs and dosages indicated by the elevated ePAD.

Drug delivery device12delivers each of the one or more selected drugs to the patient at the selected dosage as a function of control signal30(190) as described above. Furthermore, as described above, the results of adjusting the drug therapy may be reflected in the measured ePAD, which may be used to further adjust the drug therapy. Thus, system10may use feedback continually to monitor ePAD, determine the patient's activity level, and select drugs and adjust dosages as a function of the ePAD and the determined activity level (192).

Because pressure monitor32can measure ePAD during each cardiac cycle, drugs may be selected and the dosage of the drugs may be adjusted as often as on a beat-to-beat basis. The present invention is not however, limited to beat-to-beat drug and dosage adjustment. Nor is the present invention limited to measuring ePAD each cardiac cycle. Nor is the present invention limited to selecting drugs and adjusting dosages on the basis of a single ePAD measurement. ePAD may be measured and drugs and dosage may be selected at any frequency or on any basis. The drugs and dosages may, for example, be selected periodically, where the period between selections is longer than the period between ePAD measurements. For example, in some embodiments of the present invention, the drugs and dosage may be selected on the basis of the average of the ePAD values measured during the period between selections.

Input/output devices42and44allow a person, such as the patient's physician, to exchange information with processor26, pressure monitor32and drug delivery device12. Remote distribution link42provides a channel for downloading data from the patient over a telephone line or over the internet, for example. RF telemetry44provides immediate access to the data on a dedicated channel. Typically, a patient is required to visit the physician's office when data are to be downloaded via RF telemetry44. In some embodiments of the present invention, collected ePAD values, delivered drugs, dosages, delivery dates, delivery times and the like can be downloaded from the patient, and can then be processed as events, trends, or the like.

The information exchanged may include programming instructions. Processor26may be programmable by a physician via input/output devices42and44. Memory28may be used to store the instructions programmed by the physician. The programming may reflect, for example, the physician's judgment as to the appropriate drugs and dosages for the one or more drugs to be delivered to a patient over a range of ePAD values. The programming may also reflect, for example, the physician's judgment as to the appropriate drugs and dosages for the one or more drugs to be delivered in light of the determined activity level.

The correspondence between ePAD on the one hand, and drugs and dosages on the other could be stored in memory28as a look-up table that maps ePAD values or ranges of ePAD values to the appropriate drugs and dosages. When processor26receives a measured ePAD value via pressure signal40in such an embodiment, processor26then finds drugs and dosages corresponding to the measured pressure value by looking up the measured ePAD value in the table. The relationships between ePAD and dosages may also be described as curves, or as equations that defines curves.

In some embodiments of present invention where the patient's activity level is considered when deciding whether to modify the drug therapy, the activity level may be implemented as a threshold. For example, if the activity sensor output and/or the heart rate exceed a threshold value, the processor may disregard an elevated ePAD and control drug delivery device12to deliver the same drugs at the same dosages. In other embodiments, the correspondence between ePAD and activity level on the one hand, and drugs and dosages on the other could be stored in memory28as a look-up table that maps ePAD values, activity sensor output values, and heart rates to the appropriate drugs and dosages. When processor26receives a measured ePAD value via pressure signal40, an activity sensor output47, and a heart rate in such an embodiment, processor26then finds corresponding drugs and dosages by looking up the measured ePAD value, activity sensor output47, and heart rate in the table. The relationships between ePAD, activity sensor output, heart rate, and dosages may also be described as curves, or as equations that defines curves.

FIGS. 5,7and9are for purposes of illustration. How drug selection and dosages correspond to measured ePAD values depends on the drug at issue. The correspondence may also depend upon the patient's particular needs and how well the drugs cooperate with one another.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, therefore, that other expedients known to those skilled in the art or disclosed herein may be employed without departing from the invention or the scope of the claims.

The invention further includes within its scope the methods of making and using the systems described above. These methods are not limited to the specific examples described above, but may be adapted to meet the needs of a particular patient. These and other embodiments are within the scope of the following claims.

In the claims, means-plus-functions clauses are intended to cover the recited structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Thus, although a nail and a screw may not be structural equivalents in that a nail employs a cylindrical surface to secure wooden parts together, whereas a screw employs a helical surface, in the environment of fastening wooden parts a nail and a screw are equivalent structures.