Gas powered system for performing remote ischemic conditioning

A device for performing a remote ischemic conditioning treatment. The device includes an inflatable cuff and a cartridge which is a source of gas for inflating the cuff. A first valve controls the flow of gas from the cartridge to the cuff so as to maintain a predetermined pressure in the cuff during an ischemic period. A second valve allows gas to escape from the cuff during a reperfusion period of the remote ischemic conditioning treatment. A controller which may be battery-powered is used to control the opening and closing of the valves. The cartridge may contain a gas, or materials which, under certain conditions, react to produce a gas. The chemical reaction may be initiated by an electrical pulse or signal from the controller.

FIELD

This invention relates generally to systems for performing remote ischemic conditioning, and more particularly, to a gas-powered system for performing remote ischemic conditioning.

BACKGROUND

Ischemic diseases are significant causes of mortality in industrialized nations. It is well established that tissue damage results from ischemia (insufficient blood flow to a tissue) followed by reperfusion (reflow of blood to the tissue). Ischemia and reperfusion cause disturbance of microcirculation with ensuing tissue damage and organ dysfunction. Organs such as the kidney, heart, liver, pancreas, lung, brain and intestine are known to sustain damage following ischemia and reperfusion.

In ischemic conditioning (IC), a tissue or organ or region of a subject's body is deliberately subjected to brief ischemic episodes, followed by brief reperfusion episodes. IC has been found to render the tissue, organ or region resistant to injury during subsequent ischemic episodes. The phenomenon of ischemic conditioning has been demonstrated in most mammalian tissues. IC is now recognized as one of the most potent innate protective mechanisms against ischemia-reperfusion (I-R) injury. IC has also been shown to improve athletic performance, to treat and prevent restenosis, to reduce heart dysfunction or failure after myocardial infarction, and to treat traumatic injury. IC may be performed prior to (pre-), during (per-) and/or following (post-) an ischemic injury or other injury which benefits from IC.

Remote ischemic conditioning (RIC), as used herein, refers to a non-invasive process of deliberately inducing an ischemic event or period (typically by occluding arterial blood flow) followed by a reperfusion event or period (typically where blood is allowed to reperfuse) that is typically performed on an upper or lower limb or on a region of the body that is remote from an organ or tissue that is intended to benefit from the process itself. RIC may be contrasted with local IC which involves blood flow occlusion and reperfusion in a tissue or organ or region of the body to be protected from an existing or a future anticipated ischemia/reperfusion injury and is typically an invasive procedure. An example is local IC of the heart prior to cardiac surgery.

RIC may be performed as a single cycle (i.e., one ischemic event followed by one reperfusion event) or as multiple cycles. Multiple cycles include but are not limited to two, three, four, five or more cycles. The one or multiple cycles, when performed consecutively without significant delay, are referred to as an RIC regimen or treatment.

The blood flow restriction (or occlusion) typically takes the form of an applied pressure to the limb that is sufficient to occlude blood through the limb. In some instances, the occlusive blood pressure is above systolic pressure (i.e., supra-systolic pressure). It may be about 5, about 10, about 15, about 20, or more mmHg above (or greater than) systolic pressure. In some instances, the occlusive blood pressure may be at or below systolic pressure. Since systolic pressure will differ between subjects, the absolute pressure needed to induce ischemia will vary between subjects. In other embodiments the pressure may be preset at, for example, 200 mmHg. The blood flow restriction may be accomplished using any method or device provided it is capable of inducing transient ischemia and reperfusion, whether manually or automatically. Such devices include without limitation a manually inflatable cuff, or an automated device as described below. The devices comprise cuffs of standard width or cuffs of greater than standard width.

The induced ischemic period is transient. That is, it may have a duration of about 1, about 2, about 3, about 4, about 5, or more minutes. Similarly, the reperfusion period may have a duration of about 1, about 2, about 3, about 4, about 5, or more minutes.

One or both upper limbs or one or both lower limbs may be used although in some instances one or both upper limbs are preferred. In some instances, RIC is performed on two different sites on the body, in an overlapping or simultaneous manner.

Devices for performing RIC are also known in the art, and include those described in U.S. Pat. No. 7,717,855 and US Publication No. 2012/0265240 A1, both of which are incorporated herein by reference in their entirety. Both systems comprise a cuff configured to retract about a limb of a subject, an actuator connected to the cuff that when actuated causes the cuff to contract about the limb of the subject to reduce blood flow therethrough, and a controller that controls the actuator according to a treatment protocol. The treatment protocol typically includes a plurality of treatment cycles, each of which may comprise a cuff actuation period during which the actuator contracts the cuff about the limb of the subject to a pressure that occludes blood flow through the limb, an ischemic period during which the actuator maintains the cuff contracted about the limb at a set pressure point to occlude blood flow through the limb, a cuff release period during which the actuator releases the cuff to allow blood flow through the limb, and a reperfusion period during which the cuff is maintained about the limb in a relaxed state to allow blood flow through the limb.

Chronic RIC means performing a RIC regimen (which itself may comprise 1, 2, 3, 4, 5, or more cycles of ischemia and reperfusion) more than once over the course of more than one day. Chronic RIC encompasses daily performance of a RIC regimen, weekly performance of a RIC regimen, bi-weekly performance of a RIC regimen, monthly performance of a RIC regimen, including performance that is more or less frequent. Chronic RIC also encompasses performing a RIC regimen every other day, every third day, every fourth day, every fifth day, or every sixth day. The RIC regimens may be identical to each other or they may differ. Chronic RIC encompasses scheduled RIC regimens (e.g., non-random RIC regimens) or random RIC regimens (e.g., performing RIC when a subject feels the need rather than on a set schedule). Chronic RIC also contemplates that more than one RIC regimen may be performed on a single day.

SUMMARY

In one aspect, a device for performing remote ischemic conditioning includes an inflatable cuff configured to encircle the limb of a user, a cartridge containing a gas, a manifold providing fluid communication between the cartridge and the cuff, a first valve disposed between the cartridge and the cuff to control the flow of gas from the cartridge to the cuff, a second valve in fluid communication with the cuff which, when open, allows gas in the cuff to escape from the cuff, and a controller configured to open and close the first and second valve to regulate the flow of gas to and from the cuff to implement a remote ischemic conditioning treatment having at least one period of ischemia and one period of reperfusion. In one embodiment, the device includes a third valve in fluid communication with a cuff which is configured to open in response to an over-pressure event. The device may also further include a pressure monitor, and the controller and pressure monitor may maintain a cuff pressure between preselected pressure limits during an ischemic period of the remote ischemic conditioning treatment. The cartridge may contain gas in a gaseous state or in a liquified state. Multiple cartridges may also be provided in other embodiments. Where multiple cartridges are employed, the number of cartridges may equal the number of cycles in the remote ischemic conditioning treatment. In another embodiment, the cartridge may contain chemicals which, when activated by the controller, react to produce gas. This chemical reaction may be initiated by sending a signal from the controller to the cartridge. In another embodiment, the device also includes a pressure monitor which senses pressure in the cuff and/or the manifold, and opens a third valve when the pressure in the manifold or in the cuff exceeds a predetermined value. The cartridge may be disposed in a housing on the cuff, or within the cuff.

In another aspect, a device for performing a remote ischemic conditioning protocol includes an inflatable cuff configured to encircle a limb of a user, a housing attached to the cuff, at least one cartridge containing a gas or a gas-producing material, a manifold disposed between the cartridge and the cuff to provide fluid communication between the cartridge and the cuff, at least one valve disposed between the cartridge and the manifold to control the flow of gas from the cartridge to the manifold, a second valve in fluid communication with the cuff and the manifold for allowing gas within the manifold and/or the cuff to escape therefrom when in an open condition, a controller configured to control the opening and closing of the first valve and the second valve to control the flow of gas to and from the cuff to permit the cuff to be inflated during an ischemic period and to be deflated during a reperfusion period as part of a remote ischemic conditioning treatment, and a battery to provide power to the controller. The housing may include a switch to initiate a remote ischemic conditioning treatment and the like to indicate the status of the treatment. The cartridge may contain gas in a liquified form. The cartridge may also contain chemicals which react to produce a gas. The chemical reaction may be initiated by an electrical pulse sent from the controller. The device in another embodiment may comprise multiple cartridges, each cartridge being associated with a different ischemic period of a remote ischemic conditioning treatment. The cartridges may be either disposed within the housing or within the cuff.

It should be appreciated that all combinations of the foregoing aspects and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein.

The foregoing and other aspects, embodiments, and features of the present teachings can be more fully understood from the following description in conjunction with the accompanying drawings.

DETAILED DESCRIPTION

The illustrative embodiments described herein are not necessarily intended to show all aspects of the invention. Aspects of the invention are not intended to be construed narrowly in view of the illustrative embodiments. It should be appreciated that the various concepts and embodiments introduced above and those discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any particular manner of implementation. In addition, it should be understood that aspects of the invention may be used alone or in any suitable combination with other aspects of the invention.

Many existing RIC devices rely on a battery to power a pump that inflates the cuff. The pump system used to inflate the cuff in these devices requires a considerable amount of power for operation. While some of the required power is for control purposes, the pump itself consumes the majority of the power. This high power consumption requires a fairly large battery pack. The combined size and weight of the pump and batteries may be substantial. Battery shelf life also is a concern. Shelf life is relatively limited, perhaps a year without charging or a few years without replacement. Battery powered devices are suitable when there are opportunities to charge the battery, such as in ambulances or in fixed, medically supervised locations. However, in an emergency or home use application, it would be desirable for the device to have a long shelf life, perhaps 10 years, be as compact as possible and not require an external charger. Similar requirements exist for an emergency RIC device available in public places (like emergency cardiac defibrillators (AED's)) such as in office buildings, in shopping malls and aboard aircraft. Field military use is another example where a rugged, compact, simple-to-use device with an extended shelf life would be highly desirable.

In one aspect of the invention, these requirements are met by eliminating the need for a pump and associated batteries to accomplish cuff inflation, resulting in a substantially smaller, lighter device with an increased shelf life.

In another aspect of the invention, additional electrical power requirements, that result from the illumination of a number of LEDs that indicate control functions, are obviated by reducing the LED count to a single LED indicating that the unit is active.

The present invention provides a non-electrically powered source of gas of sufficient capacity to complete the RIC cycle, thus obviating the need for an electromechanical air pump. One embodiment of such a source of gas is a small gas cartridge similar to those used in carbonation systems. This type of cartridge can be filled with a variety of gases including nitrous oxide (liquid phase), carbon dioxide (liquid phase), nitrogen (gas phase) and argon (gas phase). While liquid phase gases are somewhat more compact, gas phase systems such as nitrogen and argon have specific advantages. Being in a gas phase at the storage pressure eliminates the need to specifically orient the cartridge to prevent discharge of liquid into the control circuit, and to volatilize the liquid. As a result, the use of a gas phase cartridge allows for operation at lower ambient temperatures. Nitrogen and argon are desirable because they are inert and in gas phase at the storage pressures required to provide a reasonably compact reservoir. Either a single cartridge may be provided that has the gas capacity for all inflation cycles or multiple gas cartridges may be provided, one for each inflation cycle. For multiple cartridges, each is triggered at the start of an inflation cycle.

In another embodiment of the present invention, a non-electrically powered source of gas may include a cartridge that uses a chemical reaction to generate the gas pressure required to perform the RIC procedure. Either a single chemical reaction chamber cartridge may be provided with adequate capacity for all inflation cycles, or multiple cartridges may be provided, each having capacity for a single inflation cycle. For multiple cartridges, each is triggered at the start of an inflation cycle. The gas generation materials may be incorporated into the interior of the cuff bladder obviating the need for some control mechanisms. If the provided reaction chemicals produce gas in excess of that required to provide a single inflation of the cuff, a pressure release valve limits the inflation pressure to a desired value, such as 200 mmHg. A valve may be provided to release the pressure after the desired duration of cuff inflation. The inflation cycle of the cuff may be initiated by an electrical pulse from the controlling microprocessor. If the reaction generating the inflating gas volume is exothermic, adequate protection in the form of insulation or the like is provided to prevent injury to the user. Reactions similar to that used in inflating automotive airbags may be used to generate the gas required to inflate the cuff. Other chemical reactions that might be suitable are known to those skilled in the art.

In another aspect of the invention, further reduction in electrical power requirements may be achieved by simplifying the pneumatic control systems. Pressure control in the cuff may be achieved by the use of two magnetically latched valves, one to control the incoming gas pressure and one to provide venting. Magnetically latched valves require only a very brief current pulse (on the order of a millisecond) to change state from open to closed or closed to open. Once the state change has occurred, no application of current is required to maintain the state.

In yet another aspect, the requirement for a battery in the system may be completely eliminated. Some of the energy from the compressed gas may be utilized to generate electrical current to provide power to the microprocessor based control system and valving. A piezoelectric generator may be incorporated into the system to provide adequate power to provide logic and control functions.

In yet another aspect, the microprocessor control and electro-mechanical valving may be replaced with purely pneumatic logic. Flow and pressure control are managed with pneumatic logic incorporated into a micro-fluidic chip containing timing, pressure control and valving functions.

In yet another aspect, the device may include systems to prevent unintended activation of the device, as it is likely that for home emergency use, the device would be accessible to children or subject to rough treatment. In one embodiment a simple rotary switch may incorporate a squeeze-to-unlock feature similar to that used on many household chemical or drug containers.

In yet another aspect, connectivity to web based or other monitoring systems may be provided to alert emergency personnel that the device has been activated and that a medical emergency has occurred. A Bluetooth or Wi-Fi connection may enable such connectivity.

In yet another aspect, an audible alarm indicating activation of the device may be provided for home use. Either an electronic annunciator may be activated when the device is activated or a “whistle” may be provided by diversion of some of the gas available from the reservoir.

In yet another aspect, automatic activation of the device may be achieved when it is placed on the limb. Such activation may be achieved by positioning of the activation switch such that it achieves electrical or mechanical activation when the cuff is wrapped and locked into position on the limb.

The reduction in size and complexity provided by the aforementioned embodiments and the requirement of a single use permit a unitary construction wherein the cuff and inflation and control elements are provided in a preassembled format, and may be disposable.

Turning now to the figures, several embodiments are described in further detail.

FIG. 1illustrates one embodiment of a system2for RIC. System2includes an inflatable cuff4and a controller10. In one embodiment, a housing11of controller10may be permanently attached to cuff4so that cuff4and controller10form a single unit. Housing11may be attached to cuff4in any known manner, such as by molding, glue, stitches, rivets, screws and the like. In one embodiment, housing11for controller10may be molded integrally with cuff4. In these embodiments, typically, cuff4and controller10are designed for a single use, and are disposable once the use has completed. In other embodiments, controller10may be removably attached to cuff4, such as shown in U.S. application Ser. No. 13/088,243 filed Apr. 15, 2011, which is herein incorporated by reference in its entirety. Also, in other embodiments, system2could include two or more cuffs and associated controllers which are the same as or different from cuff4and controller10and which could be used with the same limb as cuff4on different limbs of the same person.

Typically, controller10of this invention includes a button or switch12for stopping or starting an RIC treatment, and an indicator light14which indicates whether the treatment has been initiated, whether the treatment is in progress, or whether, when the light is not illuminated, the treatment has stopped. Light14typically is an LED. Both switch12and light14may be displayed on the front face of housing11. Other control features, and other displays, may be used in conjunction with controller10, such as lights indicating the progress of the treatment and providing an indication of the pressure, if desired.

One aspect of this invention will now be described with particular reference toFIG. 2.FIG. 2is a schematic drawing illustrating an embodiment of this aspect which utilizes a single gas cartridge for inflating cuff4for performing the RIC treatment. InFIGS. 2-5, dashed lines represent an electrical connection, while solid lines represent a gas line or manifold. Device40may include a single gas cartridge42, a manifold44, a coupler46for coupling gas from cartridge42to manifold44, valves52,56and58and a pressure monitor54. Some embodiments may also include a pressure regulator55. Manifold44is pneumatically coupled to a valve30in cuff4(seeFIG. 6) which permits inflation of the bladder20in cuff4(FIG. 6). Device40also may include a power source, such as battery48and a suitably programmed microcontroller50. Microcontroller50is programmed to control the operation of device40. Battery48typically is a conventional dry cell, non-rechargeable battery, although battery48could be a rechargeable lithium ion battery or other suitable battery. Either a 6 volt, a 9 volt or a 12 volt battery may be used. One battery is preferred, although more than one battery may be used for some applications. Valves52and56are controlled by microcontroller50. Valve52is opened when it is desired to inflate cuff4during an ischemic period, and is closed when cuff4is fully inflated. Valve56is opened when it is desired to deflate cuff4during a reperfusion period. Valves52and56may be magnetically latched valves. Such valves are preferred because they require less power from the battery. Only a very brief current pulse on the order of a millisecond is required to open or close the valve. Once the valve has been opened or closed, no application of current is required to maintain the valve in that open or closed state since the valve is maintained in its state using a magnetic latch. A commercially available example of such a valve is provided by The Lee Company, a Lee Series 120 Solenoid Valve.

There may be an additional safety valve58. Valve58only opens when the pressure within the cuff4or within the manifold44exceeds a predetermined value for which valve58is set. So long as the pressure within the cuff4or within the manifold44remains within a desired range, safety valve58remains closed. Valve58is preferably a known mechanical valve, since it will open regardless of whether there is a battery failure or other current failure, but valve58may also be a magnetically latched valve, or any other suitable valve. If valve58is a magnetically latched valve, it would open in response to an condition measured by pressure monitor54and would be electrically connected to microprocessor50(not shown).

Cartridge42typically is a small gas cartridge similar to those used in carbonation systems. Cartridge42may be filled with nitrous oxide which typically is in a liquid phase, carbon dioxide which typically is in a liquid phase, nitrogen which typically is in a gas phase, or argon which is typically in a gas phase. Other suitable gases may also be used. In some embodiments, gas phase systems such as nitrogen and argon are preferred, since no specific orientation of the cartridges is required to prevent discharge of the liquid into the control circuit. Also, since the propellant is already in a gas phase, device40may be used at lower ambient temperatures, since heat is not required to convert the liquid into gas. In addition, the nitrogen and argon are inert and in gas phase at the storage pressures required to provide a reasonably compact reservoir. For example, a commercially available compressed argon cartridge (iSi group 4.5 gram, 14 ml water capacity) is approximately 18.6 mm in diameter and 83 mm in length. Such a cartridge has adequate volume to inflate the cuff4at least 5.8 times. This is more than adequate to perform a typical RIC treatment.

Conventional gas cartridges42may have extremely high gas pressures within. Such pressures could be of the order of 2-3000 pounds per square inch. With such cartridges, in some embodiments, a pressure regulator55may be positioned between cartridge42and valves52and54and cuff4, to regulate the pressure in manifold44to protect valves52and54and cuff4from the effects of extreme pressures.

In operation, a medical professional, some other person or a user, wraps cuff4about the arm or leg of a person on whom the RIC treatment is to be performed (i.e., a user). Switch12is then pressed, which initiates the treatment. A signal is sent from the microcontroller50to valve52, which opens in response and permits gas to escape from cartridge42through coupler46, through manifold44and into bladder20through valve30. Cuff4then inflates. During this time, valves56and58remain in a closed position. Pressure monitor54monitors the pressure in the manifold44and therefore in cuff4. When the pressure reaches the level required to occlude blood flow in the person's limb (typically at or above systolic, although sub-systolic pressures could be used), microcontroller50closes valve52. Valve52remains closed as do valves56and58, until the ischemic period has been completed. This ischemic period is typically greater than one minute, may be five minutes, or may be greater than five minutes. The actual duration of the period depends on how the microcontroller is programmed, and the particular use for which device40is intended. Once the ischemic period is complete, microcontroller50opens valve56to permit the gas to escape from cuff4into the atmosphere. The microcontroller retains valve56in the open position during the reperfusion period for the duration programmed into the microcontroller. Typically, this duration is greater than a minute, may be five minutes, or greater than five minutes. Once the reperfusion period is complete, valve56is closed by microcontroller50, and microcontroller50again opens valve52to repeat the cycle. This cycle may be repeated as many times as is programmed in the microcontroller, and for which there is gas available in cartridge42. In a typical RIC treatment, there are 4 cycles of alternating ischemia and reperfusion, although greater or fewer numbers of cycles may be used.

If at any time during a treatment there is a system failure which causes an condition that exceeds the pressure for which safety valve58is set, valve58may open to prevent any injury to the user. Such an condition may be caused by a battery failure or blockage in relief valve56. Another possible cause of an condition is a failure of valve52such that it does not close when the desired pressure has been reached in cuff4or in manifold44. If valve58is a mechanical valve, it does not depend on battery power to open, and will open even if there is a battery failure.

In this embodiment, all of cartridge42, manifold44, coupler46, valves52,56and58, pressure monitor54, battery48and microcontroller50may be contained within housing11of controller10. However, it should be understood, that certain of these elements could be outside housing11. For example, cartridge42could be placed on or within cuff4in direct communication with bladder20in cuff4. Such placement would be particularly desirable where controller10is detachable from cuff4so that cuff4may be disposable, and controller10may be reusable for a second procedure.

Another embodiment of this aspect of the invention will now be described with reference toFIG. 3. InFIG. 3, device60may include a single gas generation cartridge62, a manifold64, a coupler66, a battery68, a microcontroller70, valves72,76and78and a pressure monitor74. Some embodiments may also include a pressure regulator75for the reasons previously discussed with respect to pressure regulator55. Device60is similar to device40except that gas generation cartridge62contains chemicals, that when activated, produce a chemical reaction that generates the gas necessary to inflate bladder20of cuff4. Coupler66couples the outlet from cartridge62to valve72. Valve72, when open, communicates with manifold64which communicates with bladder20of cuff4through valve30to inflate cuff4. Pressure monitor74monitors the pressure in manifold44and cuff4. Valve76is opened when it is desired to deflate cuff4, typically during a reperfusion period. Valve78is a safety valve which opens during an over-pressure event to prevent any injury to a user. Microcontroller70controls the operation of valves72and76, while battery68provides the necessary current to run microcontroller70and to open and close valves72and76. In this embodiment, battery68may also provide the current necessary to initiate the chemical reaction in gas generation cartridge62. Valves72and76may be magnetically latched valves, while valve78, like valve58, may be a mechanical relief valve, or a magnetically latched valve or any other suitable valve.

Gas generation cartridge62may include any of a number of compounds that react to produce the required volume of gas. Cartridge62may contain a single chemical reaction chamber, or multiple reaction chambers. For multiple chambers, one chamber is triggered at the start of each inflation cycle for an ischemic period. In either embodiment, should the amount of gas that is produced be in excess of what is required to inflate cuff4to the desired pressure, it may be released through safety valve78. If the reaction generating the gas is exothermic, steps must be taken to insulate the cartridge from the user to prevent injury to the user by providing insulation around cartridge62.

In one embodiment, chemicals used in automotive air bag gas generators may be used to generate the gas required to inflate cuff4. Reactions used in known air bag gas generators produce a sufficient amount of nitrogen gas for RIC treatments. In one example, a mixture of NaN3, KNO3, and SiO2may be used in cartridge62. A series of three chemical reactions inside cartridge62to produce nitrogen gas to inflate cuff4. The reactions may be initiated by an electrical charge or pulse from battery68which ignites the mixture. The resulting chemical reaction creates the high temperature condition necessary for NaN3to decompose and release nitrogen gas. The KNO3and SiO2remove the sodium metal, which is a potentially harmful byproduct of the decomposition of NaN3, by converting the sodium metal to a harmless material. First, the sodium metal reacts with potassium nitrate (KNO3) to produce potassium oxide (K2O), sodium oxide (Na2O) and additional nitrogen gas. This additional nitrogen gas can also be used to inflate cuff4. The foregoing metal oxides react with silicon dioxide (SiO2) in a final reaction to produce silicate glass which is harmless and stable, and can readily be discarded.

In another embodiment, hydrogen peroxide may be used to generate oxygen gas as the hydrogen peroxide decomposes into oxygen and water in cartridge62in the presence of a catalyst.

Operation of this embodiment of device60is similar to the operation of device40. First, cuff4is wrapped about the arm of a user. To initiate an RIC cycle, the user presses switch12, which causes light14to be illuminated on controller housing11. Switch12causes an electrical pulse to be sent to cartridge62which initiates the reaction just described above. When the gas is generated, microcontroller70opens valve72. The gas emitted from gas generation cartridge62passes through coupler66, and valve72into manifold64. Thereafter, gas passes into bladder20of cuff4through valve30. Valves76and78remain closed during this time. When pressure monitor74determines that the pressure in manifold64and cuff4is at the proper level to occlude blood flow, valve72is closed, and the pressure is maintained in cuff4at the desired level for the ischemic period. Once the ischemic period has expired, valve76is opened by microcontroller90and the gas is vented to the atmosphere during the reperfusion period. The cycle is then repeated as discussed above until the number of predetermined cycles of RIC programmed in microcontroller70have been performed. Typically, four such cycles are performed with ischemic and reperfusion periods of greater than a minute, five minutes, or greater than five minutes. Valve78will open automatically if the pressure in manifold64or cuff4exceeds a desired level.

Another embodiment of this aspect will now be described with respect toFIG. 4, which is a schematic drawing of a device80employing multiple gas cartridges. Device80includes cartridges82a-d, valves92a-d, valves96and98, pressure monitor94, manifold84, microcontroller90and battery88. In some embodiments, device80may also include a pressure regulator95for the reasons already discussed with respect to pressure regulator55. Device80typically, but not necessarily, includes one gas cartridge for each cycle of the RIC treatment. For purposes of illustration, it is assumed that the RIC treatment includes four cycles of ischemia and reperfusion of approximately 5 minutes each, however, it should be understood that more or fewer cycles of greater or shorter duration may also be used. In this illustrative embodiment, there are four gas cartridges,82a,82b,82cand82d. Each cartridge82a,82b,82cand82dmay be the same as cartridge42of device40except that cartridges82a-dmay be smaller and have a smaller gas capacity as each is needed only to supply gas for one ischemic period. Each cartridge has an associated corresponding valve92a,92b,92cand92d. Valves92a,92b,92cand92dare coupled by a manifold84to valve30of bladder20. Each of valves92a,92b,93cand92dmay be a magnetic latched valve, as described above, or may be any other suitable valve. There is also a relief valve96which, when opened by microcontroller70, allows gas to escape from cuff4during each reperfusion period. Valve96may also be a magnetically latched valve, or any other suitable valve. Finally, there is a safety valve98which serves as a relief valve should excess pressure occur in the cuff or in the manifold84. Preferably, valve98is a mechanical valve, although, like valve58, valve98may be a magnetically latched valve or any other suitable valve.

In this embodiment, all of cartridges82a-dmay be contained within housing11of controller10, or, in an alternative embodiment, the cartridges may be mounted internally to or on the surface of cuff4. If cartridges82a-dare mounted in or on cuff4, manifold84also may be mounted on cuff4.

In operation, cuff4is wrapped about the limb of a user, and switch12is depressed, illuminating light14. In response, microcontroller90sends a signal to open valve92a, releasing gas from cartridge82ainto manifold84which then conducts the gas to bladder20via valve30of cuff4, initiating the first ischemic period. Once the appropriate pressure is measured by pressure monitor94, valve92ais closed by microcontroller90and remains closed during the first ischemic period to occlude blood flow in the limb. After the appropriate time has passed, say, for example, greater than one minute, five minutes, or greater than five minutes, valve96is opened by a signal from microcontroller90, and the gas is exhausted from cuff4for the duration of the reperfusion period, which typically is greater than one minute, five minutes, or greater than five minutes. At the end of the first reperfusion period, valve96is closed by a signal from microcontroller90, and valve92bis opened by microcontroller90, releasing gas into cuff4. This process is repeated for each cycle in the RIC treatment, by sequentially opening and closing valves92b,92cand92dfor each cycle. Valve96is opened to exhaust the gas from cuff4at the completion of the RIC treatment. Valve98serves as a relief valve should an over-pressure condition occur in manifold84or cuff4.

Yet another embodiment of this aspect of this embodiment will now be described with respect toFIG. 5, which includes multiple chemical gas cartridges, typically one cartridge for each period of ischemia. For purposes of illustration only,FIG. 5shows four cartridges for four periods of ischemia and reperfusion. However, it should be understood that there may be more or fewer periods of ischemia and reperfusion and therefore more or fewer cartridges.

Device100includes chemical gas cartridges102a,102b,102cand102d. Cartridges102a,102b,102c, and102dare shown inFIG. 5to be embedded within cuff4. However, it is to be understood that cartridges102a-dinstead may be disposed within housing11, as shown for device80inFIG. 4, or attached to the exterior of cuff4. If cartridges102a-dare embedded within or attached to cuff4, insulation (not shown) may be deployed about the cartridges to prevent injury to the user. InFIG. 5, each cartridge102a-dis in direct gas communication with the interior of bladder20in cuff4through valve30. Device100also includes valves106and118, pressure monitor114, manifolds104and105, microprocessor110and battery108. As each cartridge102a-dis selectively activated, gas is fed directly to bladder20by manifold104. Although not shown, a valve and a pressure regulator could be installed between each cartridge102a-dand bladder20to protect against uncontrolled or high pressures, but such valves and regulators may not be necessary when the cartridges are embedded within cuff4. Valve106, which is also coupled to bladder20of cuff4by second manifold105, allows release of gas from cuff4upon a signal from microprocessor110. Valve106typically is a magnetically latched valve as discussed previously, although other electrically actuated or mechanically actuated valves may be used. Safety valve118and pressure monitor114are also coupled to manifold105. Valve118serves to release any over-pressure that may occur in bladder20of cuff4or manifold105. Valve118may be a mechanical valve, or like valve58, may be a mechanically latched valve or any other suitable valve. Each cartridge102a,102b,102cand102dmay be identical to cartridge62in device60, except that cartridges102a,102b,102cand102dmay be smaller and have less capacity, and they require no valves or couplers. Cartridges102a-dmay contain the same chemicals used to produce gas as previously described with regard to cartridge62.

In operation, as in the other embodiments, the RIC treatment is initiated by actuating switch12, which illuminates light14. In response, microcontroller110sends an electrical signal to cartridge102awhich initiates the chemical reaction to produce the necessary gas. The gas is conducted by manifold104to bladder20in cuff4. Cuff4is inflated and is maintained in the inflated condition for the ischemic period, which may be greater than one minute, five minutes or greater than five minutes. Pressure in cuff4is regulated by valve106in response to a pressure measured by pressure monitor114. If too great a pressure is measured by pressure monitor114, microcontroller110opens valve106to reduce the pressure. At the end of the ischemic period, valve106is opened, releasing gas from cuff4. At the end of the reperfusion period which typically is greater than one minute, five minutes, or greater than five minutes, valve106is closed by microcontroller110, and a signal is sent by microcontroller110to cartridge102bto initiate a chemical reaction to produce gas for the second ischemic period of the treatment. The same process for cartridge102ais repeated for cartridges102b,102cand102d.

In another aspect, an embodiment of cuff4will now be described with respect toFIG. 6. Cuff4may be axially rigid while being soft or non-irritating to the skin. Cuff4may include an inner layer16, a layer18, and at least one selectively inflatable bladder20disposed between layers16and18, as depicted inFIG. 6. In other embodiments, multiple bladders20may be employed. Cuff4may be adapted to encircle a limb of a user. Axis15represents the approximate center of a circular configuration formed when cuff4is wrapped about a user's limb. An axial direction of cuff4corresponds to the approximate direction of axis15. Cuff4has a longitudinal direction extending down the length of cuff4which is substantially perpendicular to the above defined axial direction. Cuff4may also be intended to be a disposable item for use with a removable or non-removable controller10. Inner layer16typically is positioned adjacent to, and often in contact with, the skin of a user. Since inner layer16may be in contact with skin, the inner layer may be made from a soft and/or non-irritating material. Inner layer16may be made from a knit, woven, or felted cloth. The cloth may include either natural or synthetic materials. Possible cloths include brushed polyester, brushed nylon, and/or other suitable materials as would be apparent to one of skill in the art. Alternatively, inner layer16may be made from a foam. In some embodiments, inner layer16may be further adapted to provide moisture absorption, wicking, and/or breathability to cuff4.

In some embodiments, cuff4may include two sections22spaced apart in a longitudinal direction and an intermediate section24disposed between sections22. Intermediate section24may be constructed to have a greater rigidity than sections22. The increased rigidity of the intermediate section24may be created either by an inherent material property difference, a difference in the physical construction (e.g. a thicker section and/or inclusion of reinforcing features), or both. In one embodiment, intermediate section24may include a substantially flat outer surface25for attachment to controller10. Intermediate section24may also include an inner surface26which is curved in the longitudinal direction of the cuff4. The curved inner surface26may be constructed so as to generally conform to the curvature of a limb. In some embodiments, the size and curvature of the cuff4may be suited for a variety of sizes and ages of patients ranging from neonates to obese adults. Cuff4may also be sized for attachment either to an arm or a leg. Intermediate section24may be constructed from thermosetting plastics, thermoforming plastics, and/or foamed materials. Sections22and intermediate section24may be integrally formed with one another, or they may be formed separately and subsequently joined using any appropriate method including, but not limited to, a sewn seam, ultrasonic welds, adhesives, rivets, clamping structures, and/or mechanically interlocking features. Section22may be formed of a foam material or any other suitably flexible yet strong material.

In one embodiment, cuff4may also include a plurality of reinforcing structures28substantially aligned in the axial direction of the cuff assembly. Reinforcing structures28typically may be formed in outer layer18of sections22. Reinforcing structures28provide axial rigidity to the cuff4. The increased axial rigidity provided by reinforcing structures28helps to distribute the pressure applied by cuff4in the axial direction to provide a substantially uniform pressure across the axial width of the cuff4. Reinforcing structures28may also help to prevent kinks in cuff4when it is placed around the arm or leg of a user. Reinforcing structures28may be spaced apart in a longitudinal direction to permit the cuff4to easily bend around an encircled limb while still providing increased axial rigidity. Reinforcing structures28may be curved or straight in shape in the axial direction. In some embodiments, the reinforcing structures28may be integrally formed with the foam in sections22such as by the application of heat and/or pressure (e.g. thermoforming) to selectively melt and/or compress portions of the foam in sections22. The uncompressed and/or unmelted portions of foam in sections22form the raised reinforcing structures28. Alternatively, reinforcing structures28may be separately formed and subsequently joined to sections22.

Layer18may also include a cloth layer19applied to an exterior surface. Cloth layer19may be formed of a low stretch or non-stretch cloth. The low stretch or non-stretch properties may be an inherent property of the cloth selected. Alternatively, cloth layer19may be a made from thermoformable materials and may be laminated to the exterior surface of layer18. The lamination process may alter the thermoformable fabric to be a low stretch or non-stretch material. In one embodiment, the cloth may be applied to and laminated with layer18in a flat layout prior to forming reinforcing structures28. Reinforcing structures28may subsequently be thermoformed to a final desired shape. The resulting sections22may be soft and have low stretch or non-stretch properties. Furthermore, sections22may be thermoformable enabling subsequent processing steps.

Selectively inflatable bladder20may be disposed between inner layer16and layer18. Bladder20may have a valve30arranged and adapted to provide a fluid inlet to the interior of bladder20. Valve30extends through a hole32in the intermediate section24of cuff4. Valve30may be placed in sealed fluid communication with corresponding manifolds44,64,84and104of respective devices40,60,80and100. Valve30may provide pressurized gas to bladder20. In some embodiments, bladder20may be a component separate from layers16and18. Bladder20may be formed such as by bonding two separate sheets of thermoplastic polyurethane together. In other embodiments, bladder20may be formed from air impermeable layers incorporated into layers16and18of cuff4. Layers of bladder20may be bonded together in an air tight manner using any number of methods including adhesives, ultrasonic welding, beads of material around the edges, and/or other appropriate methods as would be apparent to one of skill in the art. Bladder20may also be formed as a unitary structure without separate layers.

Layers16,18,19, and bladder20of cuff4may be held together at their edges in any suitable fashion, such as by a binding material36wrapped around the edge of cuff4and sewn to cuff4, as shown inFIG. 6. Alternatively, cuff4may be held together using adhesives, rivets, ultrasonic welds, or other appropriate methods as would be apparent to one of skill in the art.

In one aspect, it may be desirable to provide a non-slip interface to prevent cuff4from moving on the limb of a user, since cuff4may be worn for protracted periods of time. To provide a non-slip interface, at least one non-slip structure34may be disposed on the face of inner layer16. The non-slip structure34may be printed, glued, sewn, applied as a bead of material using a guided tool, or by hand. The non-slip structure34may include, but is not limited to, one or more strips of silicone.

Cuff4may also include fasteners to hold the cuff on a limb of a user and to adjust the circumferential size of the cuff4when in the fitted state. Such fasteners include, but are not limited to, hook and loop fasteners, latches, ratchet mechanisms, clasps, snaps, buckles, and other appropriate structures as would be apparent to one of skill in the art. For example, the fastener may be a hook and loop fastener including a plurality of adjacent unconnected hook sections38adisposed on layer18or19and loop sections38bdisposed on inner layer16. Hook sections38amay extend in the axial direction of the cuff4. The width of each hook section38a, with respect to the longitudinal direction of the cuff, may be selected to provide a flexible cuff able to wrap around different sized limbs.

In another embodiment, cuff4may be provided as a closed, elastic circular sleeve that may be slid over an arm or leg to the appropriate position. In such an embodiment, no fasteners, such as sections38aand38bwould be necessary. Such an embodiment may include one or more elastic sections or bands to retain the cuff on limbs of varying size.

In another aspect, instead of a battery in the foregoing devices40,60,80and100, a piezoelectric generator may be provided. This piezoelectric generator may be powered by diverting some of the compressed gas either from the gas cartridges, or from the chemical cartridges. In addition, gas diverted from either the chemical cartridges or the gas cartridges could be used to generate a whistle or other like sound to indicate to the user when the device is functioning. Such a whistle could be used to replace light14. Finally, the microcontroller and the electromechanical valving may be replaced entirely with pneumatic logic. Flow and pressure control could be managed with pneumatic logic incorporated into a microfluidic chip containing timing, pressure control and valving functions.

Each of devices40,60,80and100may have additional features. For example, microcontrollers50,70,90and110may also determine blood pressure during, or as part of, an RIC treatment protocol. Microcontrollers50,70,90and110may be programmed with certain error conditions which may cause the procedure to be aborted. These error conditions may include, but are not limited to: the cuff4is not pressurized within a predefined period, such as 20 seconds, 30 seconds, 40 seconds, 50 seconds, or one minute; there is no communication between the microcontroller and the valves upon start up; there is no communication between the microcontroller and the valves for more than a predefined period, such as two, three, four, or five seconds; cuff pressure is not maintained; a cartridge continues to emit gas after a predefined period; pressure in cuff4is not near zero gage pressure within a predefined period, such as 20 seconds, 30 seconds, 40 seconds, 50 seconds, or one minute after the end of an ischemic period; pressure in cuff4is above a predetermined pressure such as 200, 220, 240 or 260 mmHg for longer than a predefined period, such as 5, 10, 20, or 30 seconds; and a cartridge does not respond after a command is sent to it by the microcontroller. The error condition may be cleared and/or the system may be reset such as by pressing switch12on the face of controller10.

In some embodiments, the control circuit of a microcontroller50,70,90and110may be programmable by a health professional and/or an end user according to a prescribed treatment protocol. Alternatively, the control circuit may only be programmed at the factory and may not be altered afterwards by the end user. The control circuitry may also include non-volatile memory for the logging and storage of treatment history. A health care professional may be able to access this memory to determine the treatment history of a user and determine compliance with a prescribed treatment regime. In another embodiment, the microcontroller may send this information via wireless, or hard wired, communication or by the internet to a separate receiver for patient records, monitoring, or call center purposes. In one embodiment, controller10may include a stop button. In some embodiments, the stop button and switch12may be incorporated into a single button or switch. Controller10may also include a hard wired and/or emergency stop button. In other embodiments, other controls may be included to allow expanded control of an RIC treatment.

In addition, controller10may include displays related to the current cycle, the number of cycles left in a treatment, whether the treatment is completed, error signals, charge of the battery, and other relevant information. In one embodiment, controller10may include a cycle time display that may indicate the remaining portion of the ischemic and reperfusion periods by using illuminated indicators arranged in a circular pattern corresponding to a full cycle. Each indicator of the time display may correspond to a set fraction of the ischemic and/or reperfusion period. When all of the indicators of cycle time display are illuminated, the cycle is complete. Alternatively, the indicators of cycle time display may start a cycle fully illuminated and sequentially turn off as the cycle proceeds. When each indicator of cycle time display is dark, the particular cycle is complete. Cycle time display could also be arranged in other linear, or non-linear, shapes corresponding to a full cycle. Controller10may also include a current cycle display, or a digital numeric display, indicating whether the current cycle is the first, second, third, or other cycle. A procedure complete indicator may be illuminated with a solid color or it may blink when the RIC treatment is complete to indicate the end of the procedure. An error display may indicate when an error has occurred by blinking or being fully illuminated. Alternatively, an error display may blink in a preset pattern or display a particular color to indicate which error has occurred.