阅读说明：本技术 用于确定患者的颅内顺应性的系统 (System for determining intracranial compliance of a patient ) 是由 奥弗·巴尔内亚 欧马尔·多伦 于 2017-11-16 设计创作，主要内容包括：一种用于确定一患者的颅内顺应性的系统,包含：一体积适应器,具有一可扩展的隔间；至少一感测器,用于测量所述患者的颅内压力；以及一控制器,与所述体积适应器进行操作连通,并配置为：接收所述患者的一心动周期的测量值；识别所述患者的所述心动周期的一选定的部分；与所述心动周期的所述部分同步,指示所述体积适应器改变一体积；从所述至少一感测器接收多个颅内压力测量值,并识别所述体积变化对颅内压力的一影响；以及根据所述影响来生成一体积压力关系,以指示所述患者的所述颅内顺应性。(A system for determining intracranial compliance in a patient, comprising: a volume adapter having an expandable compartment; at least one sensor for measuring intracranial pressure in the patient; and a controller in operative communication with the volume adapter and configured to: receiving a measurement of a cardiac cycle of the patient; identifying a selected portion of the cardiac cycle of the patient; instructing the volume accommodator to change a volume in synchronization with the portion of the cardiac cycle; receiving a plurality of intracranial pressure measurements from the at least one sensor and identifying an effect of the volume change on intracranial pressure; and generating a volumetric pressure relationship from the effect to indicate the intracranial compliance of the patient.)

1. A system for determining intracranial compliance in a patient, the system comprising: a volume adapter having an expandable compartment;

at least one sensor for measuring intracranial pressure in the patient; and

a controller in operative communication with the volume adapter and configured to:

receiving a measurement of a cardiac cycle of the patient;

identifying a selected portion of the cardiac cycle of the patient;

instructing the volume accommodator to change a volume in synchronization with the portion of the cardiac cycle;

receiving a plurality of intracranial pressure measurements from the at least one sensor and identifying an effect of the volume change on intracranial pressure; and

generating a volumetric pressure relationship from the effect to indicate the intracranial compliance of the patient.

2. The system of claim 1, wherein: the volume adapter is sized and shaped to be introduced into a cerebral ventricle.

3. The system of claim 1, wherein: the portion of the cardiac cycle of the patient is a diastolic phase of the cardiac cycle.

4. The system of claim 1, wherein: the portion of the cardiac cycle of the patient is a systolic phase of the cardiac cycle.

5. The system of claim 1, wherein: the portion of the cardiac cycle of the patient is a maximum of a systolic phase of the cardiac cycle.

6. The system of any one of claims 1 to 5, wherein: the controller is configured to: receiving measurements of an additional cardiac cycle of the patient;

identifying a selected portion of the additional cardiac cycle of the patient;

instructing the volume accommodator to change an additional volume in synchronization with the selected portion of the additional cardiac cycle of the patient;

receiving a plurality of intracranial pressure measurements from the at least one sensor and identifying an effect of the additional volume on intracranial pressure; and

generating a volume pressure relationship from the effect of the volume change and from the effect of the further volume to indicate the intracranial compliance of the patient.

7. The system of claim 3, wherein: the controller is configured to:

identifying a systolic phase of the cardiac cycle of the patient;

instructing the volume accommodator to change an additional volume in synchronization with the systolic phase of the cardiac cycle of the patient;

receiving a plurality of intracranial pressure measurements from the at least one sensor and identifying an effect of the additional volume on intracranial pressure; and

generating a volume pressure characteristic from the effect of the volume change and from the effect of the further volume to indicate the intracranial compliance of the patient.

8. The system of any one of claims 1 to 5, wherein: the measurements of the cardiac cycle include a plurality of intracranial pressure measurements from the at least one sensor.

9. The system of any one of claims 1 to 5, wherein: the system includes a cardiac measurement sensor; and

wherein the measurements of the cardiac cycle comprise a plurality of electrocardiographic measurements received from the cardiac measurement sensor.

10. The system of any one of claims 1 to 5, wherein: the controller is configured to indicate a change in volume of the volume adaptor according to an order of a plurality of changes in volume, the order determined using the intracranial compliance of the patient.

11. The system of any one of claims 1 to 5, wherein: the volume is between 0.01 cubic centimeters and 2 cubic centimeters.

12. The system of any one of claims 1 to 5, wherein: the volume is between 0.05 cubic centimeters and 0.5 cubic centimeters.

13. The system of claim 1, wherein: the volume is about 0.5 cubic centimeters.

14. The system of any one of claims 1 to 5 or 13, wherein the volume change is effected within 10 to 100 milliseconds.

15. A method of operating a system for determining intracranial compliance in a patient, the method comprising the steps of:

providing a system comprising:

a volume adaptor having an expandable compartment sized and shaped to be introduced into a ventricle;

at least one sensor for measuring intracranial pressure in the patient;

a processor configured to transmit a plurality of control signals for controlling the volume adaptor; the method comprises the following steps:

receiving a measurement of a cardiac cycle of the patient;

identifying a selected portion of the cardiac cycle of the patient;

changing the volume of the volume accommodator by a volume in synchronization with the portion of the cardiac cycle;

receiving a plurality of intracranial pressure measurements from the at least one sensor and identifying an effect of the volume on intracranial pressure;

generating a volumetric pressure relationship from the effect to indicate the intracranial compliance of the patient.

16. The method of operation of claim 15, wherein: the portion of the cardiac cycle of the patient is a diastolic phase of the cardiac cycle.

17. A method of operation as claimed in claim 15 or 16 wherein: the method comprises repeating the varying, the receiving a plurality of intracranial pressure measurements, and the generating steps at different cardiac cycles of the patient.

18. A method of operation as claimed in claim 15 or 16 wherein: the measurements of the cardiac cycle include a plurality of intracranial pressure measurements from the at least one sensor.

19. A method of operation as claimed in claim 15 or 16 wherein: the measurements of the cardiac cycle include a plurality of electrocardiographic measurements from the at least one sensor.

Technical field and background

In some embodiments of the invention, the invention relates to measuring and/or influencing a cerebral blood perfusion, and more particularly, but not exclusively, to influencing said cerebral blood perfusion by a change in intracranial pressure.

U.S. patent application publication No. 2015/0005800 discloses "a significant feature of a device 10 according to this invention that measures an intracranial pressure (ICP) during each cardiac cycle of a patient, the intracranial pressure acting in cerebrospinal fluid (CSF); and determining the amount of change in a volume of a bag mounted to the implantable device 10 and inserted into a ventricle of the patient, based on a specific algorithm and the obtained measured pressure, to adapt the pulsation of the cerebrospinal fluid to the requirements of a hydrocephalus syndrome treatment. In particular, the device 10 is designed to control the amount of change in the volume of the pouch so as to drain a specific amount of the cerebrospinal fluid from the ventricle during a systole and return a similar amount of the cerebrospinal fluid back into the ventricle during a diastole of the cardiac cycle. "

U.S. patent application publication No. 2016/0052737 provides a "drainage system comprising a ventricular catheter, a drainage catheter, and a positive displacement pump operative to actively drain cerebrospinal fluid from a plurality of ventricles of a brain of a patient. "

U.S. patent application publication No. 2010/0318114 discloses "treating a patient for blood diversion due to cerebral venous theft (cerebral venous steal) by increasing a cerebral venous pressure of the patient and being instructed to eliminate the cerebral venous theft. This increase in the cerebral veins repairs a collapsed cerebral vascular system, thereby increasing cerebral blood flow. The increase in cerebral venous pressure may be achieved by using an occlusion catheter in the superior vena cava or the internal jugular vein, using an external compression in the jugular vein, or any other suitable mechanism. During the treatment, the occlusion can be precisely controlled, which may be a function of the cerebral blood flow, and after the treatment, the patient may experience a lasting effect, since the cerebral vascular system no longer collapses. "

U.S. patent publication No. 8,956,379 discloses "devices and systems that alter an intracranial compliance, a cerebral blood inflow, and/or an intracranial pressure pulsatility/waveform by oscillating contraction and expansion of a compressible composition in cranial or spinal cavities such that they increase an intracranial volume. The contraction and expansion of the compressible composition in the oscillatory compliance devices may be attributable to intracranial pressure in an individual as a result of expansion and compression of a reservoir mediated by a contractility of a heart or driven by a pump following a biorhythmic pace. The invention also relates to methods of protecting the brain of an individual from an abnormal arterial pulsation and altering the cerebral blood inflow of an individual by using the devices and systems of the invention. The plurality of oscillating compliance devices may be used to treat a variety of diseases and/or symptoms characterized by altered/abnormal intracranial compliance, cerebral blood flow, and/or intracranial pressure pulsatility/waveforms, including hydrocephalus, stroke, dementia, and migraine, vasospasm, congestive heart failure, extracorporeal cardiopulmonary circulation, or carotid endarterectomy.

Disclosure of Invention

Some embodiments of the invention may be illustrated by one or more of the following embodiments. It is noted that features from one example may be combined with features from another example to provide further exemplary embodiments of the invention.

Example 1. a method of influencing cerebral perfusion in a patient by repeatedly changing a volume of a volume adapter introduced into a skull volume of the patient, the method comprising:

estimating the time or an indicator of said time of a systolic cerebral blood inflow forming part of a cerebral blood flow cycle during a cardiac activity of said patient;

reducing a volume of the volume adapter to a volume reduced state in synchronization with the time at which the cerebral blood inflow is estimated to reach a volume amount sufficient to reduce an intracranial pressure in the cranial volume, thereby increasing a flow rate of the cerebral blood inflow; and

increasing a volume of the volume adapter to a volume increasing state relative to the volume decreasing state, wherein the volume is above 20% of a volume of the volume decreasing state during less than 30% of the cerebral blood flow circulation.

Example 2. the method of example 1, further comprising: estimating a time of cerebral blood outflow during said cardiac activity of said patient, and wherein said increasing is performed in synchronism with said estimated time of cerebral blood outflow, thereby increasing said intracranial pressure in said cranial volume such that a flow rate of said cerebral blood outflow is increased.

Example 3. the method of example 1, further comprising: estimating a time of a diastole in the cardiac activity of the patient, and wherein the increasing is performed in synchronism with the diastole to increase an outflow of venous blood, followed by a further reduction to increase the cerebral perfusion, all in the same cycle.

Example 4. the method of example 3, wherein the increasing is performed more than one third of the cycle before the decreasing.

Example 5. the method of example 1, wherein the increasing is performed less than one third of the cycle before the decreasing.

Example 6. the method of example 1, wherein the narrowing is completed before 10 milliseconds after the start of the systolic phase.

Example 7. the method of example 2, wherein the increasing is provided at a rate of about 0.05 to about 1 ml/ms.

Example 8. the method of example 1, wherein the increasing is initiated before a time of cerebral blood outflow.

Example 9. the method of example 1, wherein the estimation of time is based on an electrocardiogram signal of the patient.

Example 10. the method of example 1, further comprising: monitoring the patient over a period of time exceeding one hour, and detecting a physiological input of the patient by the monitoring, and varying one or both of a degree of the reduction and a time of the reduction in accordance with the physiological input.

Example 11. the method of example 1, further comprising: monitoring the patient over a period of time exceeding one hour, and detecting a physiological input of the patient by the monitoring, and varying one or both of a degree of the increase and a time of the increase relative to the contraction in accordance with the physiological input.

Example 12. the method of example 10, wherein the detected physiological output comprises one or more of cerebral blood flow, cerebral perfusion pressure, intracranial pressure and integral values, time derivatives and/or composite numbers thereof.

Example 13. the method of example 1, further comprising: introducing the adaptor into the skull volume and draining a portion of cerebrospinal fluid from the skull volume prior to an initial increase in the volume of the adaptor or in the same cycle.

Example 14. the method of example 13, wherein the initial increase comprises: the addition is performed in synchronism with the further removal of cerebrospinal fluid over a plurality of cycles.

Example 15. the method of example 13, wherein the initial increase comprises: the increase is made during a diastole portion of the cycle.

Example 16. the method of any of examples 1 to 15, the method comprising: determining a plurality of initial settings for the volume adapter, the plurality of initial settings including both the volume and the time.

Example 17. the method of example 16, wherein determining the setting of the plurality of initial times comprises: determining a shortest or a near-shortest delay time between said increasing and said decreasing, wherein below said delay time a clinical efficacy is significantly impaired.

Example 18. the method of any of examples 1 to 15, wherein the volume adapter has a baseline debulking volume having at least 1 milliliter of fluid.

Example 19. the method of any one of examples 1 to 15, wherein the increasing comprises: filled with an incompressible fluid.

Example 20. the method of any one of examples 1 to 15, wherein the increasing comprises: increasing a pressure in a compressible fluid in an expander.

Example 21 a method of affecting cerebral perfusion in a patient by repeatedly changing a volume of a volume adapter introduced into a ventricle of the patient during a cycle of cranial cavity pressures, the method comprising:

estimating a time of cerebral blood outflow during a cardiac activity of said patient; and

expanding a volume of the volume adapter in synchronization with the estimated time of cerebral blood outflow to achieve an amount of volume sufficient to increase an intracranial pressure in the ventricle to increase a flow rate of the cerebral blood outflow, wherein the expanding is performed during less than 30% of a cerebral blood flow circulation time.

Example 22. the method of example 21, wherein reducing the volume is performed after the expanding to allow perfusion from multiple arteries before the blood flows into the brain during a cardiac contraction.

Example 23. according to the method of example 21, the method further comprises: estimating a time of cerebral blood inflow during the cardiac activity of the patient, and reducing a volume of the volume adapter in synchronization with the estimated time of cerebral blood inflow while reducing the intracranial pressure in the ventricle, thereby increasing a flow rate of the cerebral blood inflow.

Example 24. the method of example 21, wherein the expanding is performed in an first 60% of a diastolic phase of the cycle.

Example 25. the method of example 21, wherein the expanding is performed in a later 37% of a diastolic phase of the cycle.

Example 26. according to the method of example 21, the method further comprises: a physiological input of the patient is detected and a determination is made as to whether to change an extent and/or time of the expansion and/or contraction after the expansion and/or during a sustained expansion based on the physiological input.

Example 27. the method of example 26, wherein the decision often occurs every five minutes.

Example 28. the method of example 21, wherein the ventricle is a space of cerebrospinal fluid.

Example 29. the method of example 28, wherein the ventricle is found to have a mechanical influence on at least a portion of an arterial vasculature of the patient.

Example 30. the method of example 29, wherein the ventricle is found to have a mechanical impact with at least a portion of a venous vasculature of the patient.

Example 31 the method of example 29, wherein the venous vasculature is a plurality of venules of the patient.

Example 32. the method of example 21, wherein the flow of the cerebral blood inflow and/or the cerebral blood outflow is increased by increasing the cerebral blood volume in a range of 5 to 30%.

Example 33. the method of example 21, wherein the increase in intracranial pressure is in a range of 2 to 10%.

Example 34 a system for affecting brain perfusion in a brain of a patient, the system comprising:

a volume adaptor having an expandable compartment sized and shaped to be introduced into a skull of the patient, the volume adaptor operating by transitioning between a reduced state sized to substantially reduce an intracranial pressure and an expanded state sized to substantially increase the intracranial pressure;

at least one sensor for measuring a physiological output of the patient; and

a processor in operative communication with the volume adapter and having instructions to: predicting a time of at least one of a cerebral blood inflow and a diastolic phase of the brain based on the physiological input; and transitioning the volume adapter to the contracted state in synchronization with the time of cerebral blood inflow, wherein the processor is configured to maintain the adapter in a non-contracted state for less than 50% of a duration of a cardiac cycle, and the processor is configured to apply the transition for at least 100 of 1000 consecutive cardiac cycles.

Example 35. the system of example 34, the processor further comprising instructions to predict a time of cerebral blood outflow based on the physiological input, and to transition the volume adaptor to the expanded state in synchronization with the time of cerebral blood outflow.

Example 36. the system of example 34, comprising a pump operable to transition the adaptor from the contracted state to the expanded state in less than 50 milliseconds.

Example 37. the system of example 34, wherein the expandable compartment contains a fluid.

Example 38. the system of example 34, wherein the processor has instructions to control an extra-ventricular drain in conjunction with activating the pump to provide the transition.

Example 39. the system of example 34, wherein the volume adapter has a maximum volume of between 3 to 6 milliliters.

Example 40 the system of example 34, further comprising a physiological sensor, and wherein the processor has instructions for adjusting at least one operating parameter and/or at least one time parameter of the pump in response to an input from the sensor.

Example 41 the system of example 40, wherein a controller has instructions to continuously adjust a set of operating parameters of the system in response to a patient physiological response.

Example 42. the system of example 40, wherein the time parameter comprises an interval between the expanding and the contracting, and wherein the pump parameter comprises an expansion volume.

Example 43. the system of any one of examples 34 to 42, wherein the deformable compartment comprises a non-compliant wall.

Example 44. the system of any of examples 34 to 42, wherein the controller has instructions to gradually expand the volume adaptor to reach a first expanded state at points in time when a pressure in the brain is low.

Example 45 the system of any of examples 34 to 42, wherein the controller has instructions to automatically identify an initial set of operating parameters by attempting a series of parameter settings.

Example 46. the system of any of examples 34 to 42, wherein the controller has instructions to automatically generate a pressure-volume curve to determine a compliance of the brain.

Example 47 a method of affecting brain perfusion in a patient by repeatedly changing a volume of a volume adapter introduced into a ventricle of the patient, the method comprising:

estimating a time of a cerebral blood inflow and/or a cerebral blood outflow in a cardiac activity of the patient related to a cerebral blood flow circulation; and

reducing or expanding a volume of the volume adapter in synchronization with the time to achieve an amount of volume sufficient to change an intracranial pressure in the ventricle to increase a flow rate of the cerebral blood flow.

Example 48. a method of controlling volume changes in a brain of a patient, the method comprising:

determining a change or expected change in volume of a fluid in the brain; and

the fluid is automatically added or removed in synchronization with the expected amount of change and in response to the determination in a polarity opposite the change.

Example 49 the method of example 48, wherein the increasing is at a diastolic trough of the brain.

Example 50 the method of example 48, wherein the altering and one of the adding or removing are performed in a compartment sealed from the cerebral fluid.

Example 51. the method of example 48, wherein the synchronization is contained in a same cardiac cycle.

Example 52. the method of example 48, wherein the changing or the anticipating changes are performed manually or naturally.

The following is another set of examples of some embodiments of the invention.

Example 1. a method of affecting brain perfusion in a patient by changing a volume of a volume adapter introduced into a ventricle of the patient, the method comprising: identifying a time of cerebral blood inflow in a cardiac activity of the patient; reducing a volume of the volume adapter in synchronization with the identified time of cerebral blood inflow to achieve a volume amount sufficient to reduce an intracranial pressure in the ventricle, thereby increasing a flow rate of the cerebral blood inflow.

Example 2. the method of example 1, further comprising: identifying a time of cerebral blood outflow during the cardiac activity of the patient, and expanding a volume of the volume adapter in synchronization with the identified time of cerebral blood outflow while increasing the intracranial pressure in the ventricle, thereby increasing a flow rate of the cerebral blood outflow.

Example 3. the method of example 2, wherein the expanding is provided at a speed of about 0.5 to about 1.5 ml/sec.

Example 4. the method of any of examples 2 to 3, wherein the expanding is initiated before a prediction of the time of cerebral blood outflow.

Example 5. the method of any of examples 2 to 4, wherein the narrowing is initiated before a prediction of the time of cerebral blood inflow.

Example 6. the method of any of examples 2 to 5, further comprising: a physiological input of the patient is detected, and a degree of the expansion is changed based on the physiological input.

Example 7. the method of any of examples 1 to 5, further comprising: a physiological input of the patient is detected, and a degree of the reduction is varied based on the physiological input.

Example 8. the method of any of examples 6 to 7, wherein the change in the degree of expansion and/or the degree of contraction occurs over an interval of time of more than about 5 seconds.

Example 9. the method of any of examples 6 to 7, wherein the change in the degree of expansion and/or the degree of contraction occurs over an interval of time of more than about 1 minute.

Example 10. the method of any of examples 6 to 9, wherein the detecting of the physiological input comprises: measuring a cerebral blood flow of the patient.

Example 11. the method of any of examples 6 to 10, wherein the detecting of the physiological input comprises: measuring a cerebral perfusion pressure of the patient.

Example 12. the method of any of examples 1-11, wherein the identification of the time of cerebral blood inflow and/or cerebral blood outflow is based on an R-wave measured by an electrocardiogram identified by the patient.

Example 13. the method of any of examples 1 to 12, further comprising: a portion of cerebrospinal fluid is drained from the ventricle prior to an exchange.

Example 14. the method of any one of examples 1 to 13, wherein the ventricle is a space of cerebrospinal fluid.

Example 15 the method of example 14, wherein the ventricle is found to have a mechanical influence on at least a portion of an arterial vasculature of the patient.

Example 16. the method of example 14, wherein the ventricle is found to have a mechanical influence on at least a portion of a venous vasculature of the patient.

Example 17. the method of example 16, wherein the venous vasculature is a plurality of venules of the patient.

Example 18. the method of any of examples 1-17, wherein the flow rate of the cerebral blood inflow and/or the cerebral blood outflow is increased by increasing the cerebral blood volume within a range of 5 to 30%.

Example 19. the method of any one of examples 2 to 18, wherein the increase in intracranial pressure is in a range of 2 to 10%.

Example 20. the method of any one of examples 1 to 19, wherein the intracranial pressure reduction is in a range of 2 to 20%.

Example 21. the method of any of examples 1 to 20, further comprising: discontinuing said reducing when said intracranial pressure in said patient is detected as having a value below a predetermined threshold.

Example 22. the method of any of examples 2 to 21, further comprising: discontinuing said expanding when said intracranial pressure in said patient is detected as having a value that exceeds a predetermined threshold.

Example 23 a method of affecting brain perfusion in a patient by changing a volume of a volume adapter introduced into a ventricle of the patient, the method comprising: identifying a time of cerebral blood outflow during a cardiac activity of the patient; expanding a volume of the volume adapter in synchronization with the identified time of cerebral blood outflow to achieve a volume amount sufficient to increase an intracranial pressure in the ventricle to increase a flow rate of the cerebral blood outflow.

Example 24. according to the method of example 23, the method further comprises: identifying a time of cerebral blood inflow in the cardiac activity of the patient, and reducing a volume of the volume adapter in synchronization with the identified time of cerebral blood inflow while reducing the intracranial pressure in the ventricle, thereby increasing a flow rate of the cerebral blood inflow.

Example 25. the method of example 23, wherein the expanding is provided at a speed of about 0.5 to about 1.5 ml/sec.

Example 26. the method of any of examples 23 to 25, wherein the expanding is initiated before a prediction of the time of cerebral blood outflow.

Example 27. the method of any of examples 24 to 26, wherein the narrowing is initiated before a prediction of the time of cerebral blood inflow.

Example 28. the method of any of examples 23 to 27, further comprising: a physiological input of the patient is detected, and a degree of the expansion is changed based on the physiological input.

Example 29. the method of any of examples 24 to 28, further comprising: a physiological input of the patient is detected, and a degree of the reduction is varied based on the physiological input.

Example 30. the method of any of examples 28 to 29, wherein the change in the degree of expansion and/or the degree of contraction occurs over an interval of time of more than about 5 seconds.

Example 31 the method of any of examples 28 to 29, wherein the change in the degree of expansion and/or the degree of contraction occurs over an interval of time of more than about 1 minute.

Example 32. the method of any of examples 28 to 31, wherein the detecting of the physiological input comprises: measuring a cerebral blood flow of the patient.

Example 33. the method of any of examples 28 to 32, wherein the detecting of the physiological input comprises: measuring a cerebral perfusion pressure of the patient.

Example 34. the method of any of examples 23-33, wherein the identification of the time of cerebral blood inflow and/or cerebral blood outflow is based on an R-wave measured by an electrocardiogram identified by the patient.

Example 35. the method of any of examples 23 to 34, further comprising: a portion of cerebrospinal fluid is drained from the ventricle prior to an exchange.

Example 36. the method of any of examples 23-35, wherein the ventricle is a space of cerebrospinal fluid.

Example 37. the method of example 36, wherein the ventricle is found to have a mechanical impact with at least a portion of an arterial vasculature of the patient.

Example 38 the method of example 37, wherein the ventricle is found to have a mechanical impact with at least a portion of a venous vasculature of the patient.

Example 39. the method of example 37, wherein the venous vasculature is a plurality of venules of the patient.

Example 40. the method of any of examples 23-39, wherein the flow rate of the cerebral blood inflow and/or the cerebral blood outflow is increased by increasing the cerebral blood volume within a range of 5-30%.

Example 41. the method of any one of examples 23 to 40, wherein the increase in intracranial pressure is in a range of 2 to 10%.

Example 42. the method of any one of examples 24 to 41, wherein a range of the intracranial pressure reduction is 2 to 20%.

Example 43. the method of any one of examples 24 to 41, further comprising: discontinuing said reducing when said intracranial pressure in said patient is detected as having a value below a predetermined threshold.

Example 44. the method of any one of examples 23 to 43, further comprising: discontinuing said expanding when said intracranial pressure in said patient is detected as having a value that exceeds a predetermined threshold.

Example 45 a system for affecting brain perfusion in a ventricle of a patient, the system comprising: a volume adaptor having an expandable compartment sized and shaped to be introduced into the ventricle, the volume adaptor being operable by transitioning between a reduced state sized to substantially reduce an intracranial pressure and an expanded state sized to substantially increase the intracranial pressure; at least one sensor for measuring a physiological output of the patient; and a processor in operative communication with the volume adapter and having instructions to: predicting a time of at least one of a cerebral blood inflow based on the physiological input; and switching the volume adapter to the reduced state in synchronization with the time of the cerebral blood inflow.

Example 46. the system of example 45, wherein the processor further comprises instructions to predict a time of cerebral blood outflow based on the physiological input and to transition the volume adaptor to the expanded state in synchronization with the time of cerebral blood outflow.

Example 47. the system of example 46, wherein the synchronization is timed to occur before the time of the cerebral outflow.

Example 48. the system of any of examples 45 to 47, wherein the synchronization is timed to occur before the time of the cerebral blood inflow.

Example 49 the system of example 45, wherein the expandable compartment contains a fluid.

Example 50 the system of example 49, wherein the fluid comprises a gas.

Example 51. the system of example 49, wherein the fluid comprises a liquid.

Example 52. the system of any of examples 45 to 51, further comprising at least one pump in fluid communication with the volume adapter.

Example 53. the system of example 52, further comprising a motor in operative communication with the pump and the processor.

Example 54. the system of any of examples 45 to 53, wherein the volume adapter is configured to be coupled to an extracerebral drainage tube.

Example 55. the system of any of examples 45-54, further comprising a sensor for measuring the cerebral blood flow.

Example 56. the system of any of examples 45-55, further comprising a pressure sensor.

Example 57 the system of any one of examples 45 to 56, wherein the deformable compartment comprises a non-compliant wall.

Example 58. the system of any one of examples 45 to 57, wherein the deformable compartment has a plurality of resilient walls.

Example 59 a method of affecting brain perfusion in a patient by changing a volume of a volume adapter introduced into a ventricle of the patient, the method comprising: identifying a time of cerebral blood inflow and/or outflow during a cardiac activity of the patient; changing a volume of the volume adapter in synchronization with the identified time of cerebral blood flow to achieve a volume amount sufficient to change an intracranial pressure in the ventricle to increase a flow rate of the cerebral blood flow.

Unless defined otherwise, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, a number of exemplary methods and/or materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the various materials, methods, and embodiments are illustrative only and not necessarily meant to be limiting.

As will be appreciated by one skilled in the art, aspects of the present invention may be embodied as a system, method or computer program product. Accordingly, aspects of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a "circuit," module "or" system. Furthermore, some embodiments of the invention may take the form of a computer program product embodied in one or more computer-readable media having computer-readable program code embodied in the medium. Implementation of the method and/or the system of some embodiments of the invention may involve performing and/or completing a plurality of selected tasks manually, automatically, or a combination thereof. Also, according to the actual instrumentation and equipment of some embodiments of the method and/or of the system of the present invention, a plurality of selected tasks could be implemented by the hardware, the software or the firmware and/or a combination thereof, for example using an operating system.

For example, the hardware for performing selected tasks may be implemented as a chip or a circuit in accordance with some embodiments of the invention. Such as the software, selected tasks according to some embodiments of the invention may be implemented as software instructions executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more of the tasks described herein are performed by a data processor, such as a computing platform for executing instructions, according to some exemplary embodiments of the methods and/or systems described herein. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile memory for storing instructions and/or data, such as a magnetic hard disk and/or a removable media. Optionally, a network connection is also provided. A display and/or a user input device, such as a keyboard or a mouse, may also optionally be provided.

Any combination of one or more computer-readable media may be utilized with various embodiments of the invention. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. The computer readable storage medium can be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of the computer readable storage medium would include the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a Random Access Memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this document, a computer readable storage medium may be any tangible medium that can contain, or store a program for use by or in connection with an instruction execution system, apparatus, or device.

The computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in a baseband or as part of a carrier wave. Such a propagated data signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. The computer readable signal medium can be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

A program code embodied on the computer readable medium and/or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, radio frequency, etc., or any suitable combination of the foregoing.

Computer program code for carrying out operations for embodiments of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C + + or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code may execute entirely on a user's computer, partly on the user's computer and as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or a server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a Local Area Network (LAN) or a Wide Area Network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet service provider).

Some embodiments of the present invention are described below with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in the computer-readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.

The computer program instructions may also be loaded onto the computer, other programmable data processing or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions provide processes for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks, which are executed on the computer or other programmable apparatus.

Drawings

Some embodiments of the invention are described herein, by way of example only, with reference to the accompanying drawings. Referring now in specific detail and in detail to the various figures, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention. In this regard, the description taken with the drawings make it apparent to those skilled in the art how the various embodiments of the invention may be practiced.

In the several figures:

FIG. 1 is a block diagram showing a high level overview of components interacting in a system and a method for actively influencing a cerebral perfusion pressure to affect a cerebral blood flow, in accordance with some embodiments of the present invention;

FIG. 2 is a flow chart illustrating a plurality of possible outcomes of a volume adapter, an intracranial pressure, and the cerebral perfusion pressure in synchronization with a cardiac cycle in accordance with some embodiments of the invention;

fig. 3 is a flow chart illustrating a method for affecting the cerebral perfusion pressure according to some embodiments of the present invention;

FIGS. 4A-4G illustrate exemplary simulations of volume changes of the volume adapter, and exemplary simulations of the intracranial blood pressure and cerebral blood flow in a control group and after being affected by actively changing the volume of a cerebral fluid, in which FIG. 4A illustrates an example of an embodiment of a sequence of volume changes of the adapter, FIG. 4B illustrates a second embodiment of a sequence, FIG. 4C illustrates a third embodiment of a sequence, FIG. 4D illustrates a simulation of the intracranial pressure example in a control group and over a period of time as affected by the method of the invention, FIG. 4E illustrates simulations of a ratio of the intracranial pressure between the control group and the invention as in FIG. 4D, FIG. 4F shows the cerebral blood flow relative to that without treatment in a control group, a simulation of the increase in cerebral blood flow over a period of time in accordance with the present invention, and FIG. 4G simulates a change in intracranial pressure over a period of time in an individual having a high reference intracranial pressure;

fig. 5A-5B are block diagrams of alternative systems for influencing the cerebral perfusion pressure according to some embodiments of the present invention, wherein fig. 5A illustrates a generalized volume adaptor and fig. 5B illustrates a specific embodiment of a volume adaptor in the form of an air balloon;

FIG. 5C is a flow diagram of a method of using feedback according to some embodiments of the invention;

FIG. 5D is a flow diagram of a method of installing a volume adapter system according to some embodiments of the present invention;

FIG. 5E is a flow diagram of a method of adapting one or more parameters of the volume adapter system according to some embodiments of the invention;

FIG. 5F is a graph showing time for an exemplary volume adapter system according to some embodiments of the invention;

FIG. 5G is a flow diagram of a method of pulsing a plurality of pulses in each cycle in accordance with some embodiments of the present invention;

FIG. 5H is a graph showing a simulation of a double pulsation effect of the volume adapter system according to some embodiments of the present invention;

fig. 6 schematically illustrates an alternative device in the form of an air balloon for influencing the cerebral perfusion pressure according to some embodiments of the present invention;

FIGS. 7A-7D illustrate various examples of the volume adapter according to some embodiments of the invention, wherein FIG. 7A illustrates a deformable catheter, FIG. 7B illustrates a pushable catheter, FIG. 7C illustrates a dual-chamber catheter, and FIG. 7D illustrates a dual-chamber catheter placed side-by-side;

fig. 8 illustrates an example of the volume adaptor in the form of a craniectomy and a membrane, according to some embodiments of the invention;

FIG. 9 illustrates an example of a venous volume adapter according to some embodiments of the present invention;

FIG. 10 is a flow chart of a method of determining a volume-pressure curve according to some embodiments of the present invention;

FIG. 11 is an example of the determined volume-pressure curve according to some embodiments of the invention;

FIG. 12A is a graph illustrating the use of dQ/dt as an indicator to assess the amount of change in cerebral blood flow in accordance with some embodiments of the invention;

FIG. 12B is a graph illustrating the use of dQ/dt as an indicator to assess the amount of change in cerebral blood flow in accordance with some embodiments of the invention;

FIG. 12C is a diagram illustrating the use of the integrated intracranial pressure (time) over a period of time to assess the efficacy of a system in accordance with some embodiments of the invention;

13A-13B illustrate various improvements in a brain condition when using a correct timing according to some embodiments of the present invention; and

fig. 14A (detailed view) and 14B (general view) illustrate the degradation of a brain condition when an incorrect timing applied to some embodiments of the present invention is used.

Detailed Description

In some embodiments of the invention, the invention relates to influencing cerebral blood perfusion, and more particularly, but not exclusively, by a change in intracranial pressure.

SUMMARY

An aspect of some embodiments of the present invention relates to influencing cerebral blood flow by periodically changing an intracranial volume and/or pressure. In some embodiments, periodic changes in the intracranial volume and/or pressure are synchronized to phases in a cardiac cycle. Optionally, timed changes in the intracranial volume and/or pressure improve a cerebral perfusion pressure and/or a flow of cerebral fluid. For example, the fluid includes blood and/or lymph. In some embodiments, the improvement in fluid flow is evidenced by an increased flow rate and/or an increased inflow volume and/or an increased outflow volume. Alternatively, multiple changes to a volume may use an expandable element, such as a balloon. In various embodiments herein, the balloon term is used as an example, but can be understood to mean any expandable element, even if not a balloon.

In one embodiment of the invention, the changes are made between a state in which the expandable element is in an expanded state and a state in which the expandable element is in a less expanded state (zero or some other inflation baseline). Optionally, the change in the plurality of states is very rapid, approximately 10 to 20 milliseconds.

In some exemplary embodiments of the invention, the changes are timed to avoid a total flattening of an intracranial pressure (ICP) or cerebral perfusion pressure (CCP) curve (e.g., the changes do not result in a peak and a trough pressure being equal or approximately equal, although the amplitude of a single peak or trough may be reduced). Optionally, the plurality of changes are timed to increase a volume during a diastole. Alternatively or additionally, the changes are timed such that an intracranial pressure peak flattens or is disrupted. Alternatively or additionally, the changes are timed to avoid increasing a volume of the expandable element during a systole. Alternatively or additionally, the changes are timed to promote a venous blood outflow during the diastole.

The use of the diastolic and systolic terms relates to the state of an arterial pulse in the brain, which is generally synchronized with the intracranial pressure (although it typically occurs a few milliseconds before it). During the systolic phase, the pressure is increased; and during diastole, the pressure decreases as a direct mechanical action of the systolic and diastolic phases in a heart, but at some point in time delayed relative thereto. It should be noted that the systolic phase (e.g., as shown by an R-wave) in the heart is typically earlier than a systolic phase in the carotid artery.

In some exemplary embodiments of the invention, the plurality of changes are timed to provide a state of reduced expansion of the expansion element during the systole.

In some exemplary embodiments of the invention, the plurality of changes are timed such that the expandable element does not expand to the maximum extent during a majority of the cycle. For example, an expanded duration of the expandable element that exceeds 20% as compared to an expanded duration of the expanded baseline is less than 80%, 60%, 30%, 20%, or a percentage of or less than a cardiac cycle or an intracranial pressure cycle.

In some exemplary embodiments of the invention, the changes are timed such that the expansion occurs within a short time (e.g., between 10 and 400 milliseconds, such as between 30 and 200 milliseconds or between 50 and 150 milliseconds) before the expandable element is de-expanded.

In some exemplary embodiments of the invention, the speed of expansion is high, for example, expanding to a maximum volume in less than 80, 50, 20, 10 or intermediate milliseconds. Alternatively, the deflation may be performed at a similar rate. Alternatively, the compaction is allowed to be slower than the expansion.

Typically, the brain is encased in a dural skull that serves as a receptacle for a fixed volume. This may create a limited space in which brain tissue, cerebrospinal fluid and systemic blood can expand before the intracranial pressure is increased. Perhaps due to the limited space, the increased intracranial pressure results in a reduction in the Cerebral Perfusion Pressure (CPP) possibly by counteracting an arterial pressure within the cerebral vessels. The reduced cerebral perfusion pressure results in a reduction of the Cerebral Blood Flow (CBF). Alternatively or additionally, the increased intracranial pressure results in a reduction in the volume of a plurality of blood vessels, which may also result in a reduction in the volume of blood due to the smaller available space, perhaps particularly during the systole characterized by an inflow of blood. Some clinical situations of the increased intracranial pressure include, but are not limited to, head trauma and/or cerebral hemorrhage.

In some embodiments, the flow of brain fluid is increased by reducing the volume of a content present in a ventricle, optionally in an active manner. For example, by introducing a volume adaptor, for example in the form of an expandable compartment, by shrinking the adaptor compartment, a volume occupied by the adaptor is released, optionally allowing the fluid in the ventricle to expand to a larger volume, eventually resulting in a reduction of fluid pressure in the ventricle. Potentially, decreasing the intracranial pressure may increase the amount of fluid that flows into a brain region, possibly by counteracting vascular pressure and resulting in an increase in the cerebral perfusion pressure.

Alternatively or additionally, the flow of brain fluid is increased by increasing the volume of the contents present in the brain ventricles, optionally in the proactive manner. Typically, an increase in the volume of the brain's contents results in an increase in the intracranial pressure due to the space bounded by the dura mater. Potentially, the intracranial pressure can help to squeeze a cerebral fluid drain, resulting in an increase in cerebral fluid outflow.

Since decreasing the brain volume may result in an increase of the brain fluid inflow and increasing the brain volume may result in an increase of the brain fluid outflow, in some embodiments a balance between improving the inflow and improving the outflow is solved. In some embodiments, a balance between increasing the inflow of fluid and increasing the outflow of fluid is addressed by synchronizing with reducing the volume to at least a portion of the systolic phase characterized primarily by the inflow of fluid and/or by synchronizing with increasing the volume to at least a portion of the diastolic phase characterized primarily by the outflow of fluid. Alternatively or additionally, the equilibrium is solved by adapting the magnitude of the increase and/or decrease of the volume, e.g. by avoiding expanding the volume to such an extent that the intracranial pressure that can stop inflow can be generated. Alternatively or additionally, the equilibrium is solved by providing a gradual transition between a reduced volume state and an expanded state, e.g. reducing sufficient pressure to allow the fluid to flow in, while creating sufficient pressure to squeeze the fluid to increase the outflow. In some embodiments, the time to decrease the volume and/or the time to increase the volume is selected to account for the balance by synchronizing the adaptation of the volume to the cardiac cycle and based on an expected blood flow compatible with phases of the cardiac cycle.

In some embodiments, a trigger point to increase and/or decrease the brain volume is based on the cardiac cycle, optionally based on an Electrocardiogram (ECG) measurement. In some embodiments, a time of the R-wave based on the electrocardiogram is used as the trigger point to increase and/or decrease the brain volume. In some embodiments, the volume is actively changed when an event in a time axis of the cardiac cycle is identified, for example, the volume is reduced when an imminent systolic pressure wave is determined. In some embodiments, the change in volume is effected prior to an expected event, such as an expected change in the inflow and/or outflow, so as to allow sufficient time for the change to occur until the event occurs.

Optionally, a direct measurement of the cardiac cycle is provided, for example by measuring the electrocardiogram, and/or measuring a pulsation, and/or measuring a blood pressure. In some embodiments, cardiac measurements are performed by a measurement probe, such as an electrode, positioned near the heart. Alternatively or additionally, the measurement is carried out by measuring the pulsation of the cerebral blood vessels, and/or by measuring the pulsation and/or the blood pressure of any region of the body. Optionally, the phases of the cardiac cycle are calibrated to compensate for any delay between a measurement location in the brain and a volume-adapted location.

Optionally, the start of the phases of the cardiac cycle is determined by an extrapolation and/or a prediction and/or a machine learning. In some embodiments, the cardiac cycle is taken from a measurement of the intracranial pressure and/or a plurality of volume fluctuations.

Typically, the change in volume to a patient's brain is when the patient is unconscious. Therefore, it is a potential advantage to monitor the effect of the volume change by detecting and/or measuring physiological inputs of the patient. In some embodiments, the physiological input is gathered after each cardiac cycle. Alternatively additionally, the physiological input is gathered after more than two of the cardiac cycles. Alternatively additionally, the physiological input is gathered after five or more of the cardiac cycles. In some embodiments, a plurality of measurements of the physiological input determine a degree of increase and/or decrease in the brain volume. Alternatively or additionally, measurements of the physiological inputs determine a rate of increase and/or decrease of the brain volume.

In some embodiments, the detection of the physiological input of the patient is used as a feedback. Optionally, these feedback measurements are used to modulate the degree of increase and/or decrease in the brain volume. For example, measurements of the physiological inputs in the form of the cerebral blood flow may indicate that the flow is too weak, and these measurements may be used to reduce the brain volume, optionally by increasing a degree of reduction of the volume adapter placed in the brain. In another example, a measurement of a plurality of the physiological inputs in the form of the brain perfusion pressure may indicate that the brain perfusion pressure is too high. These measurements can be used to increase the brain volume, optionally by increasing a degree of expansion of the volume adaptor placed in the brain (which will result in an increase of the intracranial pressure, which will result in the cerebral perfusion pressure being reduced based on the calculation of the cerebral perfusion pressure-Mean Arterial Pressure (MAP) -intracranial pressure).

In some embodiments, one or more of the following criteria are used as part of the treatment marker or as a separate treatment marker: tissue oxygenation, cerebral blood flow values, intracranial pressure values, cerebral perfusion pressure values, integrated values over time, smoothed values and/or time derivatives and/or morphology of their waveforms. Alternatively, the physiological markers associated with any of these may be used, as may other markers indicative of a brain state and/or the cerebral blood flow.

In some embodiments, the physiological input gathered at a plurality of spaced time points is longer than a duration of the cardiac cycle. Thus, in some embodiments, the mediation of the volume change is provided at a plurality of spaced time points, the plurality of spaced time points being longer than the duration of the cardiac cycle. For example, varying the degree and/or determining such a need may occur in an interval of about 5 seconds at a time. In another example, varying the degree may occur at intervals of about 1 minute each time, or for longer periods of time, such as 5 minutes, 10 minutes, 20 minutes, or intermediate or longer periods of time.

In some embodiments, the cerebral blood flow is improved by increasing the brain volume during at least a portion of the diastole, perhaps by a retrograde flow that may result in an increase in the volume of blood displaced. In some embodiments, the increase in brain volume is performed gradually. Potentially, the gradual increase will allow a longer interval until the ventricle returns to its pre-systolic configuration (expansion), and by doing so can have more time during the cardiac cycle, where the blood inflow can occur with a lesser resistance due to a more relaxed cranial apex. For example, small increases in the volume increase during the diastole, for example in a range of about 0.5 ml to about 2 ml, are configured to result in a slightly increased intracranial pressure, which may not affect multiple arterioles, but may affect a venous system by causing higher resistance to the outflow. Alternatively, it may translate into an increased perfusion pressure in the brain tissue, potentially replenishing a collateral circulation, and/or opening blood vessels in an edematous tissue, and/or improving the cerebral blood flow. It has been understood by the inventors that an increase in a range of about 0.1 ml to about 7 ml, for example 0.5 to 5 ml, can cause significant changes in the intracranial pressure in an edematous brain, and potentially changes in this range may be sufficient to apply venous congestion and recruitment upstream of the collapsed vessels.

In some embodiments, a constriction during an expansion curve is used to identify forces that may act on a delivery system and/or a drainage system. Optionally, the reduced forces on the delivery system, such as an arterial system, create more space for fluid filling, potentially further promoting the cerebral blood inflow. Optionally, the forces on the drainage system, such as a venous system, "squeeze" the blood volume out of a venous end, potentially further promoting the cerebral blood outflow.

In some embodiments, the cerebral perfusion pressure is calculated as the difference between the mean arterial pressure and the intracranial pressure. In some embodiments, and currently used for improving the cerebral perfusion pressure, the reduction of the intracranial pressure is provided, for example, by hyperventilation, and/or hypertonic therapy, and/or cerebrospinal fluid (CSF) drainage, and/or extensive drug sedation. Alternatively or additionally, an increase of the mean arterial pressure is provided, for example using an amine to increase the systemic arterial pressure. A potential drawback of the above-mentioned treatment options is that the patient will be exposed to uncontrollable side effects of systemic treatment.

In some embodiments, the cerebral perfusion pressure is changed by changing the volume of the cerebrospinal fluid in a ventricle of a patient, for example, by using an extra-ventricular device (EVD). Optionally, the extra-ventricular device is augmented by actively altering the volume of the ventricle by the volume adaptor, the volume of cerebrospinal fluid being passively drained and/or returned by the augmented extra-ventricular device. In some embodiments, once a skull of the patient is penetrated and/or once a passive and/or an active volume adapter is inserted into a brain compartment of the patient, an amount of the cerebrospinal fluid flows out of the brain compartment. In such embodiments, when the volume of the volume adaptor is reduced to a certain extent, the ventricle accommodates a volume below a reference volume, i.e. the volume before penetrating the skull and/or inserting any device.

In an adult, the cerebral blood flow is typically 750 milliliters per minute or 15 to 20% of a cardiac output. In some embodiments, the cerebral perfusion pressure is maintained at a pressure of about 50 to about 60 mm hg (or 60 to 160 mm hg), meaning that the mean arterial pressure minus the intracranial pressure falls at about 50 to about 60 mm hg. Typically, the reduction in cerebral perfusion pressure results in a reduction in cerebral blood flow. In some embodiments, if a patient has a lower level of the cerebral perfusion pressure, the intracranial pressure is actively reduced to restore the cerebral blood flow to a basic physiological level. An aspect of some embodiments of the invention relates to a plurality of active changes of the brain volume synchronized to the cardiac cycle. In some embodiments, the change in volume is provided by a volume adapter that is inserted locally into a brain compartment of a patient, optionally a ventricle filled with the cerebrospinal fluid. In some embodiments, the shrinking and/or expanding of the adaptor results in a plurality of changes in the volume of the brain compartment. In some embodiments, filling and/or draining the adaptor with a fluid in liquid form causes changes in the volume of the brain compartment. Alternatively or additionally, the filling and/or draining of the adapter with a fluid in gaseous form causes changes in the pressure of the brain compartment. In some embodiments, reducing the volume and/or the pressure of the brain compartment by expanding the volume adapter in the brain results in a decrease of the intracranial pressure at specific points in time of the cardiac cycle, which together with a flow phase of the cardiac cycle increases the brain perfusion pressure and/or improves the cerebral blood flow. Alternatively or additionally, by increasing the volume and/or the pressure of the brain compartment at a plurality of other points in time of the cardiac cycle, an increase of the intracranial pressure is caused, which together with a flow phase of the cardiac cycle increases the brain perfusion pressure and/or improves the brain blood flow.

In some embodiments, the volume adaptor comprises a balloon. In some embodiments, the balloon is inflated by a fluid, optionally a gas, when expanding the volume of the brain compartment. In some embodiments, the balloon is inflated with a liquid, optionally water and/or saline. In some embodiments, the balloon is deflated by pumping the fluid out of the range of the balloon. In some embodiments, performing deflation of the balloon includes using a change in temperature, and/or a change in volume of the balloon into which acoustic transmission is converted, and/or electrical energy.

Optionally, the volume adapter is provided in combination with an extra-ventricular drainage device. In some embodiments, the reduction and/or increase in brain volume in the ventricle containing the cerebrospinal fluid provides a suction effect in the ventricle, optionally creating a force that enhances the flow of the cerebrospinal fluid into or out of the ventricle.

In some embodiments, the balloon is filled with fluid from a reservoir. Optionally, the reservoir is located outside the patient's body. Alternatively or additionally, the reservoir is provided in the patient's body. In some embodiments, the balloon is actively filled with gas by a pump, and optionally passively vented to ambient air by releasing a valve. Alternatively or additionally, at least two pumps are provided to selectively actively fill and actively drain the balloon. In some embodiments, a motor is provided for operating at least one of the pumps. Optionally, the motor is provided outside the patient's body. Alternatively or additionally, the motor is provided in the patient's body, optionally in the brain compartment, optionally in the adaptor device.

In some exemplary embodiments of the invention, a syringe pump is used. Optionally, a rate of filling and/or emptying of the balloon is at least 10 ml/sec, at least 50 ml/sec, at least 100 ml/sec, at least 250 ml/sec, or faster or intermediate rates. Optionally, the filling and/or emptying of the balloon occurs between 1 and 50 milliseconds, e.g., between 5 and 30 milliseconds, e.g., between about 10 and 20 milliseconds. Optionally, the fastest speed is provided to allow for short inflation times. Alternatively or additionally, a slower speed is used to avoid shaking into the brain tissue.

Optionally, the volume adaptor comprises a non-compliant surface. Potentially, the non-compliant surface allows for a change in the pressure, but not the volume of the volume adaptor. Alternatively, the volume adaptor comprises a resilient surface.

In some exemplary embodiments of the invention, changes in a plurality of said volumes do not cause an overall flattening of said intracranial pressure.

In some exemplary embodiments of the invention, the inflation is timed not to occur during a period in which the intracranial pressure exceeds a particular value. Alternatively, the particular value is defined as a function of a baseline of the intracranial pressure, a peak of the intracranial pressure, or the intracranial pressure value over some portion of the cardiac cycle. Optionally, the expansion is timed not to occur during the systole. In some exemplary embodiments of the invention, the expansion and the deflation may be effected even if the intracranial pressure is between 30 and 50 mmhg.

In some exemplary embodiments of the invention, the inflation is timed to occur just before the deflation, so that most of the balloon's cycles do not inflate beyond its baseline. Alternatively, this expansion is used primarily to allow the constriction to have an effect on the brain. Optionally, an inflation duration is optimized for this effect (e.g., long enough so the deflation is effective but not too long (e.g., less than 10% of the cycle).

An aspect of some embodiments of the invention relates to optimization of multiple changes in the intracranial volume and/or pressure. In some exemplary embodiments of the invention, one or more of the maximum (minimum) volume (and/or pressure), the rate of volume (and/or pressure) change, the start of volume (and/or pressure) change, the delay time between the inflation and deflation, the duty cycle, the duration of the inflation and/or deflation, the end of volume (and/or pressure) change, the compliance of pressure and/or volume, and/or the number of pulses per cycle (the effect of the inflation/deflation) of each patient will be optimized. Optionally, the optimization is changed over a period of time, for example, in response to a plurality of parameters of the patient.

In some exemplary embodiments of the invention, the optimization comprises increasing a parameter until a desired mechanical and/or physiological effect is detected. Optionally, the increase is paused and/or reversed once determined to be an undesirable effect and magnitude.

An aspect of some embodiments of the invention relates to a volume-pressure curve measured and/or used in a patient with (suspected) cranial blood flow abnormalities. In some exemplary embodiments of the invention, the curve is estimated by injecting (e.g., inflating a intracranial balloon) a known volume at a known point in time. Optionally, the known time is the end of the diastole when the brain is draining as much fluid as possible. Optionally, this time is determined by measuring the intracranial pressure. At this point in time, the relationship between the volume increase and the pressure increase is determined. Optionally, the measurement is performed repeatedly during a plurality of cardiac cycles, optionally injecting different amounts in different cycles. Optionally, the volume of the injection is increased when the intracranial pressure is stabilized. In some exemplary embodiments of the invention, the injection is performed at a scale of 0.1 ml and up to 5 ml. In some exemplary embodiments of the invention, the measurements are additionally or alternatively applied at other points in time of the cardiac cycle, e.g. at a maximum systolic phase and/or over a time window when the injection is planned for treatment.

An aspect of some embodiments of the invention pertains to controlling the expansion of an intracranial device in conjunction with a fluid removed from the skull. Optionally, the fluid is removed prior to and/or simultaneously with expansion of the device, optionally under the control of a single controller.

In some exemplary embodiments of the invention, the removal of the fluid occurs during systole, whereas expansion of the device occurs during diastole.

In some exemplary embodiments of the invention, the device is maintained in an expanded state (e.g., between 0.1 and 0.7 ml, e.g., about 0.5 ml) for at least a portion of the entire cycle.

In some exemplary embodiments of the invention, the device is compacted back to a baseline state for each of the systolic periods and expanded (and the expansion may increase) during the diastolic period.

In some exemplary embodiments of the invention, the expansion is only allowed to increase to an amount of volume corresponding to the fluid removal amount. For example, if the removal of the fluid is halted, the maximum expansion volume is not increased.

An aspect of some embodiments of the invention relates to including more than one pulsation in at least some pressure cycles. It should be noted that a pressure in the brain (intracranial pressure) changes during a cycle that is usually coordinated with systemic blood pressure.

In some embodiments of the invention, the constriction (volume reduction) is provided just before the systolic phase to allow more blood flow into the brain. Optionally, an additional pulse is provided during diastole, e.g. the expansion is used to collapse veins and reduce the intracranial fluid. Optionally, the deflation is followed by such inflation so as to allow increased arterial blood flow.

In some exemplary embodiments of the invention, the amplitudes of the two said pulsations are different, e.g. a lower amplitude is provided for the additional pulsation. Alternatively or additionally, the shape of the two said pulsations is different. Optionally, further additional pulses (e.g., 1, 2, 3, or more) are provided during the cycle, e.g., during the diastole and/or during the systole, optionally with a volume that does not increase the intracranial pressure (or the cerebral perfusion pressure (CCP) or other pressure measurement) beyond a peak provided by a first pulse. Optionally, the number and/or timing of such pulses is determined using a search and/or an optimization process and/or is changed as a result of adjustment of the device, e.g., as described herein.

It should be noted that in some embodiments, no pre-systolic pulsation is provided, only a single (e.g., a diastolic pulsation) or multiple additional pulsations are provided.

A primary aspect of some embodiments of the invention relates to varying the volume of the fluid in the brain in synchronization with a cranial pressure cycle. In one example, the fluid is removed or injected at a known and selectably repeatable point in the cycle. This can be used to generate a pressure-volume curve. In another example, the injection and/or removal of fluid is timed to cooperate with expansion and/or deflation of an expandable intracranial element, optionally resulting in substantially zero overall change in the volume (manual input to manual output) during a cycle or during a small portion of the cycle (e.g., 500 milliseconds).

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and to the arrangements of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

High level overview

Referring now to the drawings, FIG. 1 shows a high level overview of components that interact in a system and a method for actively influencing a cerebral perfusion pressure to affect a cerebral blood flow, according to some embodiments of the present invention.

In some embodiments, a volume adaptor 101 is introduced into a patient's brain 10, optionally into a cerebrospinal fluid space, such as a ventricle with cerebrospinal fluid, a subdural location, or a spinal location. In some embodiments, the volume adaptor 101 is configured to actively increase and/or decrease its volume. Optionally, by being surrounded in a deformable environment, such as by the cerebrospinal fluid, the change in the volume of the volume adaptor 101 influences the extent to which the deformable environment is pushed against its confinement, i.e. the change in the volume of the adaptor 101 influences a pressure exerted by the ventricle, potentially influencing an intracranial pressure in a versatile manner.

In some embodiments, the intracranial pressure is affected to cause an increase in cerebral perfusion pressure, optionally also to induce a change in cerebral blood flow 150, based on the time of phases of a cardiac cycle, the changed cerebral blood flow 150 being increased by a percentage 75 over a reference cerebral blood flow 155. In some embodiments, the increase in cerebral blood flow comprises a greater volume of a blood inflow and/or a blood outflow. Alternatively or additionally, the increasing comprises increasing a flow velocity.

In some embodiments, an activity of a heart 8 is detected. Optionally, the activity detected by the plurality of electrodes provides an electrocardiogram. Alternatively or additionally, the activity is detected by a pulse measurement (e.g. in or on an artery such as the carotid artery) and/or blood pressure, optionally a cerebral blood pressure. In some embodiments, a cardiac cycle waveform is obtained from a plurality of measurements of the activity of the heart 8. Alternatively or additionally, the cardiac cycle waveform is derived by extrapolation of other measurements, such as the amount of change in the intracranial pressure. In some embodiments, the cardiac cycle waveform is predicted by a machine learning before its start. In some embodiments, the cardiocirculatory waveform includes identifying at least one event, the event being a systolic phase or a diastolic phase. In some embodiments, the recognizing includes determining a start of a phase. Alternatively or additionally, the recognizing includes predicting the onset. Alternatively or additionally, the identifying comprises determining and/or predicting a peak of a systolic wave and/or a diastolic wave.

In some embodiments, the activity of the heart 8 affects 120 the time and directionality of the volume change of the adaptor 101. Optionally, the time and direction of the volume change of the adapter 101 and a reservoir are synchronized with the cardiac activity of the heart 8. For example, when a contractile force wave is determined, the volume adaptor 101 may be deflated in order to potentially reduce the intracranial pressure and thus allow more blood volume to fill a brain compartment in the brain 10. In some embodiments, the volume adapter 101 is expanded in order to increase the volume and thus potentially make it possible for a pressure existing inside the brain compartment to help to squeeze blood, for example, during at least a part of the diastolic wave. Optionally, the volume of the accommodator 101 is maintained during a peak period between the systolic wave and the diastolic wave. Additional exemplary timing options are described above and below.

A potential advantage of synchronizing the time and amplitude of volume change (i.e., volume amount) between the adapter 101 and the heart activity is to balance between increasing the intracranial pressure and eliminating blood inflow to reduce the intracranial pressure and eliminating blood outflow. By synchronizing to the cardiac cycle, a blood flow waveform is potentially used to increase and decrease the intracranial pressure, such that the blood flow is increased for at least a portion of the time. In some embodiments, a varying proportion of the time and magnitude between the increase and decrease changes the fraction of time and quality of the flow improvement 75. For example, fig. 14A and 14B illustrate an example of a time that does not have a beneficial effect on the flow rate increase.

In some embodiments, the flow enhancement 75 comprises an increase in brain blood volume, for example, from about 0.5 ml to about 2 ml, and/or from about 1 ml to about 3 ml, and/or from about 3 ml to about 5 ml. Alternatively or additionally, the flow enhancement 75 includes an increase in cerebral blood flow velocity, for example, about 14 to 16 cm/sec in arteries and/or veins, and/or about 0.02 to 0.04 cm/sec in microvasculature. In some exemplary embodiments of the invention, parameters of a treatment are altered to achieve one or more increases or other changes in the values of the physiological parameters described above. Some exemplary methods are described below.

Results and Performance of some possible exemplary systems

Referring now to fig. 2, a flow chart illustrating a number of possible outcomes of a volume change of a volume adapter, a change in intracranial pressure, and a change in cerebral perfusion pressure in synchronization with a cardiac cycle in accordance with some embodiments of the present invention is shown.

In some embodiments, a volume adaptor 22 is reduced 222 when a pre-peak of a systolic phase is identified, i.e., when an amplitude height of a systolic pressure wave is predicted to be close to 220. In some embodiments, the intracranial pressure 24 is reduced 224 when a volume is reduced 222. As the systolic pressure wave approaches 220, the reduced intracranial pressure 24 at 224 potentially results in a lower the cerebral perfusion pressure 26, and also increases the volume so as to allow blood inflow to fill multiple cerebral delivery systems, such as the arterial and/or arteriolar systems.

In some embodiments, the reduced volume 222 is maintained throughout at least a portion of the systolic phase 240, and optionally during the entire duration thereof. In some embodiments, when the volume is maintained at 242, a pressure is maintained at 244 and 246, the 244 and 246 indicating the intracranial pressure 24 and the cerebral perfusion pressure 26, respectively. In some embodiments, during the systole, the cerebral perfusion pressure may increase due to an increase in blood inflow.

In some embodiments, the volume adapter 22 is expanded 262 during at least a portion of a diastole 260. Optionally, this results in an increase 264 of the intracranial pressure 24 and thus a decrease 266 of the cerebral perfusion pressure 26 and may result in a decrease of the overload on a drainage system, such as a cerebral venous system, potentially resulting in an increase of a blood outflow. Optionally, the cerebral venous system is a plurality of venules.

Exemplary methods for affecting cerebral perfusion pressure

Referring now to fig. 3, a flow chart illustrating a method for affecting brain perfusion pressure according to some embodiments of the present invention is shown.

In some embodiments, a volume of fluid of a ventricle is actively reduced by introducing a volume adapter into a brain compartment of a patient. Optionally, the volume is reduced 302 below a reference volume, since some cerebrospinal fluid is drained from the brain compartment during the insertion of the volume adaptor, resulting in a new lower reference volume. In general, the reduced volume of ventricular fluid results in less fluid volume in a relatively fixed volume compartment of the brain, which results in a reduction in intracranial pressure 304. Optionally, the reduced intracranial pressure results in a reduced load on a delivery system 306 that results in an increase 308 in the cerebral perfusion pressure. In some embodiments, the increased cerebral perfusion pressure at 308 allows more fluid, such as blood and/or lymph, to flow into the brain compartment. Alternatively, when 302-310 are provided in synchrony with a systolic phase of a cardiac cycle, which is primarily characterized by a high inflow, the effect of 302-308 above 310 is enhanced.

In some exemplary embodiments of the invention, the narrowing 302 is performed such that the adaptor is at its baseline volume before the start of the systolic phase. In some embodiments, the narrowing is performed continuously after the onset of the systolic phase, e.g., there is an overlap of 2% to 20% or more between the systolic phase and the partially expanded adaptor. It should be noted that a baseline state of the adapter may have a volume greater than zero, for example, to ensure that if the intracranial pressure increases or the ventricle collapses, it can do so with some minimum volume.

In some embodiments, the ventricle is actively filled with a fluid volume 312 when the systolic phase ends or alternatively when it is predicted (e.g., based on the length of the R-to-R interval and/or the shape of the pulsatile wave and/or a number of previous cycles) that it will end soon (e.g., within a time range of 0.05 to 0.2 seconds before the end of the systolic phase). Typically, an increase in volume in the fixed volume brain compartment results in an increase 314 in the intracranial pressure, which consequently increases the load on a drainage system, such as a venous system. In some embodiments, the increased load acts as a compressor to assist in the outflow of cerebral fluid. Optionally, when providing 312 to 318 in synchrony with a diastolic phase of the cardiac cycle, it is mainly characterized by a high outflow, enhancing the effect of 312 to 316 above 318. In some embodiments, the filling is provided near the beginning of the systolic phase as a preparatory step to fluid removal during and/or before the systole.

Exemplary simulation of the effects of varying intracranial pressure

Referring now to fig. 4A-4G, exemplary simulations of an intracranial blood pressure and a cerebral blood flow in a control group and after being affected by actively changing the volume of a cerebral fluid are shown, according to some embodiments of the invention.

Fig. 4A-4C illustrate examples of a sequence 400 of volume changes for an adapter. In some embodiments, the sequence 400 is synchronized to at least a portion of a cardiac cycle 420. In some embodiments, the sequence 400 is a repeating and repeating same pattern in each cardiac cycle. Alternatively, the sequence 400 is changed between cycles, optionally in accordance with a physiological input measured from a patient. In some embodiments, the physiological input is a cardiac activity, such as a plurality of cycle phases and/or a pulse and/or a blood pressure. Alternatively or additionally, the physiological input relates to measurements of a plurality of brains, and comprises the intracranial pressure and/or the cerebral perfusion pressure and/or a cerebral perfusion volume and/or a cerebral blood flow velocity.

In some embodiments, a particular profile of the sequence 400 is determined based on a particular pathology of the patient. For example, a patient with low compliance may be treated by a relatively fast and small volume-adapted transition (e.g., selecting a speed and volume based on available compliance). Optionally, the specific profile is changed in time based on the physiological input gathered during the volume adaptation and affects a plurality of subsequent cycles of the adaptation.

Optionally, the volume of the adapter is synchronized with the outflow and/or inflow of cerebral blood. In some embodiments, the cerebral blood flow is measured directly by a flow sensor. Alternatively or additionally, the cerebral blood flow is inferred from other brain and/or heart related physiological inputs.

Reference is now made to fig. 4A. In some embodiments, the volume of the volume adapter is reduced in synchronism with the inflow of cerebral blood, as shown in sections a to b, optionally starting from point a at the beginning of a systolic phase. In some embodiments, point a is synchronized to a point in time after the onset of the systolic phase. Optionally, the volume adaptor is maintained in a reduced state, as shown by the flat areas b-c, starting at point b and ending at point c, point b optionally being a point in time before a pressure peak of a contracting pressure wave. In some embodiments, point c causes an expansion period, as shown by sections c through d. Optionally, point c is timed to a point during diastole. Alternatively, point c already starts the compression allowing the cerebral blood to flow out before the start of the diastole. In some embodiments, the expansions c-d are gradual, e.g., in a range of about 0.5 to 1.5 ml/sec, optionally resulting in an overall expansion in a range of about 0.5 ml to 3.5 ml. Alternatively, the rise in the extensions c to d is steep. In some embodiments, a flat area in an expanded state is maintained after the expansion c to d, as shown in sections d to a.

Referring now to fig. 4b, an example is illustrated where the flat line regions of b to c end at a point in time at which the systolic phase ends at point c, and then at a gradual increase in volume c to a, there is no flat line region, and start again at a point a where the volume is reduced before the systolic phase.

Referring now to fig. 4c, an example is illustrated in which the changes in volume are all steep, e.g., a decrease from a to b and an increase from c to d, and between the changes, the plateau regions b to c and d to a are all maintained, optionally along substantially the entire length of the remainder of the cardiac phase.

In some embodiments, point C represents the transition from a contracted state to an expanded state in fig. 4A-4C, the determination of point C being such as to balance the allowing of inflow of the systolic phase with the outflow of the diastolic phase. For example, the balance is solved by selecting a point in time before the end of the systolic phase and/or before the start of the diastolic phase, so as to allow a sufficient pressure increase to allow the outflow, but still allow the inflow at the end of the systolic phase. Alternatively, the reduction of the volume, e.g. as at point a, starts before the beginning of the systolic phase and/or the end of the diastolic phase, in order to prepare a reduction of the pressure for the inflow, which is characteristic of the systolic phase.

In some embodiments, the flat areas are determined in a plurality of sections that feature a predominant flow pattern, i.e., substantially excluding the inflow or substantially excluding the outflow. Other shapes may also be provided, such as one or more valleys and/or peaks included in the flat line region, optionally the flat line region being a series of pulses, optionally having a volumetric amplitude of less than 50% of a pre-systolic pulse.

Fig. 4D illustrates a simulation of the intracranial pressure in a control set and over a period of time as affected by the volume adaptation, in accordance with some embodiments of the invention. An example of a decrease in the intracranial pressure following a decrease in the volume of the adapter, and an increase in the intracranial pressure following an increase in the volume of the adapter, is shown.

Fig. 13A and 13B show a potentially desirable effect of the volume change, where a pressure peak is reduced in a maximum magnitude and/or splits (into two or more smaller peaks) and/or flattens (with a smaller acute angle).

FIG. 4E simulates a ratio between the intracranial pressure in a control group 421 and a changed trend line 401, as shown in FIG. 4D. It should be noted that as the intracranial pressure increases during the diastole, it optionally does not reach the peak found in the systolic phase.

Fig. 4F shows a simulation of the increase in cerebral blood flow over time in accordance with some embodiments of the present invention relative to the cerebral blood flow without treatment in a control group. Showing an exemplary increase in the blood inflow found in a peak of the contracting pressure wave.

FIG. 4G simulates a change 402 in an intracranial pressure over a period of time in an individual having a high reference intracranial pressure 422. In some embodiments, as shown in the examples, the pressure may only decrease below the reference value and may not increase above the reference value. Generally, in the case of a high reference intracranial pressure, the effect of reducing the intracranial pressure is more pronounced.

Exemplary System for influencing cerebral perfusion pressure

Referring now to fig. 5A-5B, block diagrams of alternative systems for affecting cerebral perfusion pressure are shown, in accordance with some embodiments of the present invention, in which fig. 5A illustrates a generalized volume adaptor and fig. 5B illustrates a specific embodiment of a volume adaptor system 500 using an expander 101 in the form of an air sphere.

In some embodiments, a system includes a volume adapter 101, the volume adapter 101 being located in a ventricle 510 of a patient. In some embodiments, the volume adaptor 101 affects an intracranial pressure of the patient by changing a volume of volume inside the ventricle. In some embodiments, a controller 504 is found in operative communication with the volume adapter 101. For example, the controller 504 has a plurality of instructions that cause the shrinking of the adaptor 101. Alternatively or additionally, the controller 504 has a plurality of instructions that result in expansion of the adaptor 101. Optionally, the controller 504 is in communication with a motor located in the adaptor 101. Alternatively or additionally, the controller 504 communicates with an external motor 540, as shown in fig. 5B.

In some embodiments, the controller 504 receives input from at least one sensor 502. For example, the sensor 502 may detect a cardiac activity, such as electrocardiogram and/or pulse and/or blood pressure. Alternatively or additionally, the sensor 502 can detect the intracranial pressure and/or the cerebral perfusion pressure and/or a cerebral blood flow velocity and/or a cerebral blood flow volume (e.g., as shown by a brain sensor 520, e.g., an intracranial sensor, e.g., an intracranial pressure sensor).

In some embodiments, the controller 504 includes instructions for identifying when the heart activity is active, e.g., at about the time of a diastole, of a cerebral blood inflow. Optionally, the controller 504 operates the adapter 101 to reduce in synchronization with the time of cerebral blood inflow. Alternatively or additionally, the controller 504 manipulates the adapter 101 to expand in synchronization with the time of a cerebral blood outflow.

In some embodiments, the controller 504 further includes a plurality of instructions for predicting the inflow and/or the outflow time. Optionally, synchronicity is timed to make its changes prior to an expected flow change in operation. For example, the adaptor 101 is scaled down before or after a prediction of the inflow begins. A potential advantage of the synchronicity, which includes a time offset of the inflow and/or the outflow and/or other physiological events, is to maintain a balance of conflicting influences between the pressures during the inflow and the outflow, perfusion and/or influence various regulated cycles.

In some embodiments, at least one more sensor is provided, for example, a cerebral blood flow monitor, and/or a brain tissue partial oxygen pressure (PbtO2) monitor, and/or cerebral perfusion pressure (time) and/or a cerebral perfusion pressure integral value (e.g., an integral over time) and/or intracranial pressure (time) and/or an intracranial pressure integral value (amount of intracranial pressure/cerebral perfusion pressure (ICP/CCP)). Optionally, a plurality of calculated values from at least one of the sensors is used to determine the magnitude of the zoom out and/or the zoom out of the device. In some exemplary embodiments of the present invention, the integration value is within a period of time between 1 and 600 seconds, for example, between 5 and 10 seconds.

In some embodiments, a pressure sensor (e.g., 520) is provided for measuring pressure at least two different points on a cerebral vessel of the patient. Alternatively or additionally, at least one flow sensor is provided. Optionally, operation of the volume adapter is stopped when an undesired pressure difference and/or absence and/or other undesired fluid flow in the blood vessel is detected between the at least two different points.

Optionally, the controller 504 includes instructions to stop expanding the volume adapter 101 when the pressure sensor provides a value that exceeds a predetermined threshold, for example, more than 15 mmhg, or more than 20 mmhg, or more than 25 mmhg, or more than 30 mmhg, or more than 35 mmhg.

Optionally, the controller 504 includes instructions to stop reducing the volume adapter 101 when the pressure sensor provides a value below a predetermined threshold, for example, below 5 mm hg, or below 4 mm hg, or below 3 mm hg.

In some exemplary embodiments of the invention, the controller 504 comprises a plurality of instructions for searching for a plurality of initial values and/or a plurality of adaptive values of a plurality of system parameters.

In some exemplary embodiments of the invention, the controller 504 includes instructions for calculating a pressure-volume curve.

Generally, it should be noted that all of the methods specifically described herein, sensing, analyzing sensed signals, expanding and contracting, and determining and/or actually changing the plurality of system parameters (except possibly physically inserting the expander 101 into the skull) are performed under the control and/or notification of the controller 5024. Alternatively, a user may define multiple alarms or automatically sound an alarm in a particular situation. Optionally, the controller 504 avoids certain activities (e.g., potential life threatening, e.g., as defined by data storage) and requires human approval or instructions.

It should also be noted that while the controller 504 may be self-contained, in some embodiments, some data and/or instructions and/or decision making capability are provided at a separate unit, optionally at a remote location (e.g., at a server or in the cloud).

Referring now to fig. 5B, a block diagram of an exemplary embodiment of the volume adapter in the form of the balloon 501 is shown, according to some embodiments of the present invention. In some embodiments, the balloon 501 is expanded and contracted by at least one pump 544. Optionally, the balloon 501 contains a fluid, such as a gas and/or a liquid. In some embodiments, the pump 544 is found in fluid communication with a reservoir 540. Alternatively or additionally, the pump 544 receives gas from the ambient air surrounding the patient. In such an embodiment, a fluid inside the balloon 501 may be selectively released through a valve in the event that the reservoir fluid is unrestricted. In some embodiments, the valves are controlled by the controller 504.

In some embodiments, the pump 544 is found in operative communication with the motor 530, and the motor 530 may optionally be found in operative communication with the controller 504. In some embodiments, the motor 530 is found in the balloon apparatus. Alternatively or additionally, the motor 530 is found outside the patient's body and/or otherwise as a separate unit. .

In some embodiments, the reservoir 540 is found outside the patient's body. Alternatively or additionally, the reservoir 540 is found in the ventricle 510, optionally in a solid compartment.

In some embodiments, the balloon 501 includes a plurality of non-compliant walls. One potential advantage of using the multiple non-compliant walls is their inherent expansion limitation, which in the case of the ventricle, over-expansion can cause damage to the patient. In some embodiments, the balloon 501 comprises two layers, optionally one layer being non-compliant and optionally the other layer being resilient. One potential advantage of using an elastic layer within the non-compliant layer is that the elastic layer may more easily change its volume, while the non-compliant layer determines the expansion limit of the elastic layer.

Exemplary feedback

Fig. 5C is a flow chart of a method of using feedback according to some embodiments of the invention.

At 542, a patient is optionally diagnosed. It should be noted that different conditions may be treated differently and/or that the initial settings may be different (e.g., using a table or other computing functionality stored in the system 500).

At 544, the system 500, or at least a volume-altering portion (e.g., 101) of the system 500, or a removed portion of the system 500, is implanted in the patient, if not already implanted. Additional exemplary details are provided below with reference to fig. 5D.

In some exemplary embodiments of the invention, the implanting comprises implanting and/or connecting one or more physiological sensors, such as a plurality of intracranial or intravascular pressure sensors and/or a plurality of doppler flow sensors. Optionally, the plurality of sensors are connected to a plurality of sensor processing circuits that may or may not be part of the system 500, e.g., a plurality of standard sensing systems, such as a plurality of intracranial pressure sensing and computing systems that may include an intracranial pressure probe and generate a data output that encodes a measured intracranial pressure. It should be noted that the intracranial pressure probe may be mounted on the expander 101, for example, on or in an introducer catheter of the expander, or may be provided separately and/or alternatively implanted through a different opening into a skull.

At 546, a plurality of initial system parameters are optionally selected, for example, using the method illustrated in FIG. 5D below.

At 548, the system 500 is optionally enabled, which may include changing one or more system operating parameters, e.g., as described with reference to FIG. 5E. Optionally, the treatment is provided continuously. Optionally, a pause time is prepared for the measurement to assess a brain state, e.g., 1 to 30 minutes every 0.5 to 12 hours or every 0.5 to 4 days. The length of the pause time is selected to allow the brain to reach a steady state. In some embodiments, the treatment is over a period of, for example, 5 to 400 minutes or more in length, with a plurality of the pause times therebetween of, for example, 5 to 400 minutes or more.

At 550, the patient may abandon the system/therapy. For example, once the patient stabilizes, the intracranial pressure drops and/or based on other indications, the system may automatically, or in response to user input, begin to drop or otherwise change the amount of therapy provided. In an example, the number of treatment periods (e.g., if the treatment is not continuously provided) and/or their length (e.g., the length of each period) is reduced and/or the duration during a period is increased. Alternatively or additionally, the ratio between treatment cycles and non-cycles is reduced. Optionally or alternatively, the amplitude and/or time of the dilation is reduced so as to cause less disturbance, or to be different from, cerebral blood flow. Optionally, a setting protocol is provided in a memory, the setting protocol including a plurality of stages and different settings for different stages and/or a plurality of targets.

In some exemplary embodiments of the invention, the sensing comprises sensing a pulsation in the carotid artery. This has the potential advantage that the time at which a pressure wave reaches the brain is easily predicted and/or less variable.

Exemplary set-up

FIG. 5D is a flow chart of a method of installing a volumetric adapter system according to some embodiments of the present invention.

At 552, the device (e.g., the volume adapter 101) is inserted into a brain.

At 554, a constant volume change process is optionally initiated. It will be appreciated that the intracranial pressure in the patient is typically high. Expanding the adapter 101 may cause an additional pressure spike, which is generally undesirable. In some exemplary embodiments of the invention, a cerebrospinal fluid is removed from the brain synchronously with or prior to the expansion of the adapter 101 so as not to increase the intracranial pressure, or at least not to increase beyond a threshold value, e.g., 0.3, 0.7, 1 or 2 mmhg or an intermediate or greater value. Optionally, the cerebrospinal fluid is removed by an extra-ventricular drainage device. Optionally, the adapter 101 is mounted on such a drainage device, and the device is controlled by the system 500 to remove the required cerebrospinal fluid and/or expand the adapter 101 only in accordance with the amount of fluid actually removed by the device.

In some exemplary embodiments of the invention, the expansion is provided only during a diastole (e.g., low intracranial pressure). Optionally, the removal of fluid is performed during a cardiac contraction (e.g., high intracranial pressure). Optionally, during the systole, the accommodation period is reduced back to a bottom line of its expansion. Optionally, it does not shrink to or below the base line during introduction. Once the system is in use, expansion and contraction to the bottom line can be performed.

In one example, the balloon is inserted and inflated to an initial volume, for example, about 0.5 ml or less. Optionally, during inflation to this volume, the cerebrospinal fluid is slowly removed, and the balloon begins to slowly inflate to introduce a volume of the balloon up to a few milliliters of the depleted volume of cerebrospinal fluid, so there is no net pressure rise during the process. After this initial expansion, a first constriction and further constrictions and expansions (and optionally increasing the baseline volume) may be predefined as not increasing the intracranial pressure beyond the baseline.

In some exemplary embodiments of the invention, when the volume of the balloon is increased, the cerebrospinal fluid is continuously drained while the balloon is more inflated. This may prevent collapse of the ventricle caused by, for example, the intracranial pressure being too low, too high, or changing abruptly. Generally, it should be noted that multiple intracranial pressure mechanisms cannot distinguish the cerebrospinal fluid volume outside the balloon from the volume of the fluid inside the balloon (and thus the balloon volume). This method may allow a higher volume of the balloon to be achieved than simply expanding the balloon gradually and waiting for the cerebrospinal fluid to be redistributed in the nervous system.

In some exemplary embodiments of the invention, a cerebrospinal fluid removal device, such as a catheter having a plurality of orifices, is used as follows by utilizing the natural brain pulsation. With each heart cycle, during the systolic phase, when the balloon is deflated, some cerebrospinal fluid volume (dCSF) is "pushed" by the brain into the catheter, which acts as a conduit, with or without active suction from the brain. During the diastole, the balloon is inflated to its previously set volume plus the dCSF volume (or thereabouts), which is expelled by the brain during the systole. In net terms, the total volume of the brain is optionally unchanged, except for a greater volume of the balloon and a lesser volume of the cerebrospinal fluid. This may allow the balloon to expand and/or contract to a greater extent.

Thereafter, a plurality of initial parameters are optionally set. It should be noted that a maximum volume of the device may be changed during setting, which may require additional fluid to be removed from the brain during the setting of the parameters and not just prior to such setting.

When one or more predetermined systems and parameters are predetermined, in some exemplary embodiments of the invention, parameters that are determined to be valid and/or safe during a first phase of the system 500 are used. Desirably, a set of parameters that are both safe and effective are determined or otherwise provide a desired balance between safety and effectiveness. Optionally, one or more parameters are limited by a plurality of preset values and/or ranges, which are selected and predefined based on the diagnosis of the patient. Such values may be stored in the memory of the system 500.

A first parameter is volume. A maximum volume of the adapter 101 may determine a maximum degree of the intracranial pressure. As mentioned above, high intracranial pressures are generally to be avoided. In some exemplary embodiments of the invention, the maximum volume and/or the time of the maximum volume is selected to avoid increasing the intracranial pressure at a less than ideal point in time. It should be noted that when referring to the intracranial pressure, in many embodiments, the cerebral perfusion pressure (CCP) relating the intracranial pressure to arterial pressure can be effectively used instead.

In one method, the maximum volume is first selected and then the time is optimized. Alternatively, both the volume and one or more time parameters may be searched simultaneously

At 566, a first volume, for example, 0.1 ml or 0.5 ml, is tried.

At 558, a positive effect of the volume, e.g., an increase in the cerebrospinal fluid or a change in dQ/dt (rate of blood exchange), is determined. Such a determination may occur, for example, over a period of 1 to 100 seconds.

At 560, a number of negative effects are determined, such as an increase in intracranial pressure peak or a decrease in dQ/dt. Again, this may be detected as a trend over a plurality of cycles, for example, between 10 and 200 seconds.

In some exemplary embodiments of the invention, perfusion and/or oxygenation (or other physiological measurements as shown herein) are measured at each volume.

At 562, if the plurality of negative effects are too high, the volume can be reduced. If the front image is too low, the volume may be increased (e.g., 0.1 ml or other small amounts such as between 0.05 ml and 0.17 ml). Alternatively or alternatively, other parameters may be varied, e.g., one or more time parameters, to vary a portion of the cardiac (and/or intracranial pressure) cycle that coincides with the maximum volume.

It should be noted that the settings may include two or more sets of parameter values, such as a desired maximum volume and a second highest "allowed" volume, which may be related to certain conditions of the patient (e.g., for manual or automatic application and/or alarm generation by a caregiver) and/or allowed to be applied for a particular duration (e.g., intentionally or unintentionally, as may occur for timing).

Other parameters may also be evaluated in a similar manner at 564. It should be noted that when describing a single parameter search process, multiple search methods and multiple optimization methods may also be used, such as gradient descent, which optimize/search multiple parameters simultaneously or in an interleaved manner.

One or more of the following system parameters may optionally be changed:

(a) starting to expand;

(b) ending the expansion;

(c) a change in maximum expansion volume or volume;

(d) the speed of volume change;

(e) the slope shape of the volume change;

(f) the length of the flat area;

(g) the slope of the plateau or other non-linear shape of the plateau;

(h) starting compaction;

(i) a compaction speed;

(j) ending the compaction;

(k) tightening the slope;

(l) A duty cycle of the flattened region for deflation and/or the expanded and deflated flattened region;

(m) a delay time between inflation and deflation;

(n) minimum of spread (bottom line)

(o) pressure or systemic compliance at any or all portions of the intracranial pressure cycle; and/or

(p) physiological parameters used for the time of each event (e.g., detection of R-waves, blood pulsation waves); and

(q) the number of pulses in a cycle (as described below), each pulse possibly having a different value for any or all of the above parameters.

Experiments were performed with a pig model, some of which are also shown in fig. 12-14, and this also informs indications of potentially useful starting points for some or all of the above settings and/or ranges that were sought during the search or adjustment.

The experiments were performed on pigs (40 to 50 kg) that were anesthetized and placed flat on their back for carotid catheterization. Thereafter, as described herein, we moved the pig to a prone position for Cranial incision (Cranisal infusion), while implanting an intracranial pressure monitor, performing a ventricular ostomy (Ventriculostomy), and installing a cerebral blood flow monitor and an air balloon. The position of the balloon and the ventricular ostomy is confirmed by ultrasound.

After stability was determined, a first group of five pigs were treated as a Water poisoning model (Water poisoning model) (0.18% saline was slowly injected intravenously to cause severe hyponatremia, followed by cerebral edema resulting in a gradually increasing intracranial pressure). A second group of five pigs had an extremely slow infusion of saline which injected into the brain causing gradual hydrocephalus. In both groups, the intracranial pressure was gradually increased and the balloon apparatus was tested and shown to be generally effective in the following intracranial pressure steps: 10-15-20-25-30-35-40 mm Hg. The hemodynamics of the pigs were stable and multiple results from both groups of pigs had the same general properties. Some of the results shown herein illustrate some embodiments of the invention. It should be noted that treating a human brain may require a large volume compared to a porcine brain, but the porcine brain is considered to be a useful model for the human brain in terms of intracranial pressure and flow problems.

In some exemplary embodiments of the invention, the expansion and/or deflation of the balloon is brief, e.g., about 10 to 20 milliseconds for a volume between 0.5 to2 milliliters. Alternatively, a syringe pump is used, for example, having a piston moving at a speed of 2000 cm/sec. Optionally, a maximum speed is limited by a desire to avoid jarring the brain.

In some exemplary embodiments of the invention, it should be noted that, for example, 0.6 ml may not be effective as follows. Alternatively, the volume is at least 1.2 ml or even at least 1.8 ml. In general, a larger volume seems to be beneficial (provided it does not cause a too high intracranial pressure). As mentioned above, the volume may be adjusted as required during treatment, optionally automatically.

In some exemplary embodiments of the invention, the baseline volume of the balloon (or other expandable structure) is selected to allow a working volume even if the intracranial pressure is increased. It should be noted that in some embodiments, an important function of the balloon is its deflation, and it is desirable to ensure that this potential is maintained. In some exemplary embodiments of the invention, the initial removal of the cerebrospinal fluid allows the balloon to be inserted and inflated to such an initial baseline volume without significant effect on the intracranial pressure. For example, such a base line may be 0.5, 1, 1.5, 2, 2.5 milliliters or less or an intermediate or greater volume (e.g., additionally having a base line of 2 milliliters and an expanded volume of 1 to2 milliliters)

Optionally, such an expansion baseline allows the device to occupy space even if the ventricle collapses. Alternatively, during collapse of the ventricle (which may be short term or sporadic), the base line of the balloon may be allowed to decrease, so as to use a difference value between an old base line and the decreased base line as a volume for the expansion. Alternatively or additionally, operation of the system may be stopped during collapse of the ventricle, however, it would not be necessary to reintroduce and inflate the balloon.

In some exemplary embodiments of the invention, the balloon body expands and contracts at other points in time during an intracranial pressure cycle, optionally to a lesser amount, e.g., to maintain the expanded volume of the balloon body.

In some exemplary embodiments of the invention, an R-wave synchronized to the cardiac cycle, or an indication of carotid artery pulsation or other arteries near the cerebral arterial system, is selected. This may be the basis for all time parameters, for example, as described below. Optionally, if a heart rate changes, the time is adjusted accordingly, optionally automatically. Some parameters may be essentially independent of the heart rate (e.g., duration of contraction) and some may be linked to specific portions of the R-wave (e.g., the beginning of the contraction before the systolic period). For example, the adjustment may be proportional or at a fixed point in time relative to such events.

For example, a user may select a time based on the intracranial pressure, and the system may automatically calculate a delay time between an electrocardiogram signal or an arterial pulse and this point on the intracranial pressure wave. Optionally, the system also takes into account the speed at which a volume of the expander 101 changes. In one example, the system is set up by carotid pulsation (e.g., using a Doppler sensor), and then the time between a feature of an electrocardiogram, such as the R-wave, and the carotid pulsation is measured, so that the time can be based on the electrocardiogram.

In some exemplary embodiments of the invention, the constriction is set to begin with an increase in arterial pressure that increases in the carotid artery. In pigs, this was found to correlate with about 50 milliseconds after the detection of the R-wave from the pig's electrocardiogram. Optionally, after such setting, the system is examined (e.g., with respect to the intracranial pressure or arterial waveform) to determine that the deflation did occur just at the beginning of the pressure rise, preferably just before it. Optionally, this test is applied before the system is started (e.g., fig. 5E).

In some exemplary embodiments of the invention, the expansion of the accommodator 101 is set to occur during the diastole. Experimental evidence suggests that expansion during the systole causes a decrease in perfusion and an increase in the intracranial pressure.

In some exemplary embodiments of the invention, a test is performed prior to start-up of the system, the test comprising confirming that the expansion only occurs after the pressure peak has elapsed and optionally when the systolic phase is complete.

In some exemplary embodiments of the invention, the expansion is selected to occur as close to the contraction of the next cycle as possible, which is typically very late in the diastolic phase of the cardiac cycle. Said as close as possible does not mean that a duration of the expansion state in each case is close to zero. For example, the expanded state may have a minimum duration (depending on the patient) to facilitate fluid extraction from the brain (ablation). This may be determined by varying the duration and monitoring the cerebral blood flow or one or more other parameters.

In some exemplary embodiments of the invention, the following settings and multiple parameters are used: the detection of the R-wave is followed by the calculation of the cardiac cycle (e.g., heart rate 75, 800 ms cardiac cycle). A latency time for the compacted R-wave is then selected (e.g., 50 milliseconds depending on the arterial waveform and/or the compaction speed). The R to R segments are then detected (e.g., 800 ms in this example) and subtracted, e.g., 50 to 100 ms, to define an expansion point. This results (for an 800 millisecond cycle) in the inflation beginning at a time point of 50 milliseconds and the deflation beginning at a time point of 700 or 750 milliseconds. The time to reach the inflation and/or deflation may optionally be between 10 and 20 milliseconds.

Based on experimental results, these time parameters appear to be a useful setting, at least for some patients, for example, with an initial intracranial pressure of 25 to 30 mm hg and an initial perfusion (hamard monitor) of 20 to 30 ml/min/100 g of tissue. For example, the volume may be between 1.5 and 3 milliliters. For example, in a pig model, after the system 500 is activated, the perfusion increases by 3 to 5 ml/min/100 g of tissue and the intracranial pressure decreases by 10% to 15% on average (e.g., 25 to 30 becomes 20 to 25).

Use of exemplary feedback during treatment

Fig. 5E is a flow diagram of a method of adaptively modifying one or more parameters of a volumetric adaptation system in accordance with some embodiments of the present invention.

At 570, the system 500 is used, for example, by using a plurality of parameter sets according to fig. 5D. It will be appreciated that typically the condition of a patient will not change for only a period of time, but that there may be multiple short-term physiological changes. In some exemplary embodiments of the invention, the system 500 accommodates one or both of long term changes in the patient's condition and short term changes in physiology.

A first type of compliance is to avoid and/or reduce injury. A second type is to increase and/or maximize efficiency.

In a simplest example, multiple changes in the patient's cardiac cycle may invalidate a selection of a parameter. In another example, a gradual increase or decrease in an intracranial pressure baseline may create an opportunity to require or allow a change in a maximum volume and/or duration of inflation/deflation.

While the system 500 is in use, the patient's condition and/or one or more of the measurements in response to treatment are optionally monitored.

At 572, a positive effect of the system 500, such as an increase in the cerebral blood flow, is optionally detected. The absence of the positive effect and/or the reduction of the positive effect implies a change in the plurality of parameters.

At 574, a negative effect of the system 500 is detected, for example, a decrease in the cerebral blood flow or an increase in the intracranial pressure peak. Such negative effects imply changes in the plurality of parameters.

At 576, the monitoring of the plurality of parameters of the system 500 and/or the patient suggests that a change in the system parameters may be beneficial, e.g., an increase in volume may be acceptable if the intracranial pressure baseline is decreased.

At 578, one or more system parameters may be changed. Optionally, the change uses a predefined set of multiple parameters (e.g., delay time for simultaneous change in volume and compaction). Alternatively, only one parameter can be changed at a time. Alternatively, for example, a search method as described with reference to fig. 5D may be used.

It should be noted that the patient may have multiple sets of system parameters and/or corresponding multiple sets of allowed or desired physiological parameters. Alternatively, the use of 572 to 576 allows a different set of system parameters to be selected at 578, for example, in response to a set of measured or desired physiological calculated values (either manually or automatically). Alternatively or alternatively, a certain amount of tolerance (leeway) is provided by such a combination, e.g. a certain proportion of the cardiac circulation may be allowed without perfusion increase relative to a baseline, provided that the intracranial pressure is also maintained low.

In an example of adaptive therapy, a cerebral perfusion pressure and/or an integral value of the intracranial pressure over a period of time is used as a physiological measurement.

In some exemplary embodiments of the invention, a user may provide input such as limits, desired values, values for alarms, and/or values deemed to be therapeutic.

If such measurements do not show (any and/or sufficient, e.g., 10%) improvement above a baseline and/or above some other setting (e.g., an expected improvement or a fear of stepping back), the plurality of system parameters may be changed. In one example, the maximum volume gradually increases. For example, a lack of improvement within five minutes triggers an increase in maximum expansion of 0.1 ml. The decision on the change depends, for example, on a base line speed, such as a few minutes, and/or on the severity of an effect, such as a large adverse effect (e.g. defined by a plurality of system settings), resulting in a rapid reduction of the maximum volume.

If the change in volume (e.g., until a maximum safe value is reached) does not provide the desired improvement, the time for the inflation and deflation is changed, e.g., at a spacing of 1 millisecond relative to the R-wave. Alternatively, for example, the pitch may vary from a large size and then taper and/or vary in direction according to the effect of the variation.

Detection of a plurality of said adverse effects optionally triggers a reduction of said expanded volume, e.g. to a baseline level or below. If this is not sufficient, the expansion can be performed instantaneously in advance with respect to the change in R-wave and/or time (e.g., length) so as not to coincide with the intracranial pressure exceeding a certain value and/or a percentage of the intracranial pressure peak.

In a particular method of using an intracranial pressure integral value, the rate of change (ROC) of the intracranial pressure (time) curve for each of the cardiac cycles is compared to a previous cardiac cycle (or set of cycles) and the amount of rate of change allowed and/or provided is defined.

Optionally, such comparison uses a plurality of paired cycles, for example, a non-arrhythmic cycle, a similar heart rate cycle, a similar electrocardiographic cycle, and/or a cycle without arrhythmia.

In some embodiments of the present invention, the adaptation of the system 500 is relative to an alternative notation. For example, the system 500 adjusts and/or runs the intracranial pressure/dose integral of the cerebral perfusion pressure (time) or intracranial pressure (time)) calculated in time as a feedback with respect to timely or improper start of the system, in real-time with respect to any relevant proven perfusion or acceptable cerebral oxygenation monitoring method (e.g., cerebral blood flow monitoring, brain tissue oxygen partial pressure monitoring, etc.).

Optionally, a value of the selected marker is analyzed for a subsequent start-up within 1 to 600 seconds of the start-up of the system. Optionally, data between 60 and 3000 seconds is gathered before the start-up and/or during a low level start-up (which may not have a positive effect, but also does not have a negative effect) and used as a bottom line.

If after the start-up a poor result compared to this baseline, the synchronicity may optionally be checked and/or optimized, e.g. checking a tightening time (optionally manual). Optionally or alternatively, an inflation time is checked and/or changed to go back on the fly (e.g., in a small time interval, e.g., back to a short time, such as 30 milliseconds, after the pressure spike). Optionally, a perfusion (or other) marker is used to determine the effect of this change in the distension time and/or the contraction time. Once improvements are detected, these may be used as new parameters and/or as a key point for starting an optimization process for other parameters.

Fig. 12A-12C illustrate various exemplary methods of assessing efficacy of the use of the system 500 according to some embodiments of the present invention.

FIG. 12A shows the evaluation of dQ/dt in a pig model. The vertical lines indicate when the balloon is inflated or deflated (the deflation is just before the systolic phase). As can be seen, after operation of the system, dQ/dt was increased and also changed in the direction from-0.031 to +0.156 ml/(min 100 g sec).

FIG. 12B shows an example where dQ/dt does not become positive, but continues to increase.

FIG. 12C shows an example in which the value of the integral of intracranial pressure is used (e.g., over a period of time between successive vertical arrows). Respiratory artifacts (respiratory artifacts) are removed and a plurality of vertical arrows indicate inflation/deflation events of the balloon. As can be seen, the value of the integral of intracranial pressure decreases when the system is in use. Similar results are expected for an integrated value of cerebral perfusion pressure.

In some exemplary embodiments of the invention, morphology is used instead of using thresholds for desired values (or other methods of detecting changes with comparison values). For example, if a therapeutic target is to increase a duration of a low intracranial pressure during diastole, or to flatten or split a peak intracranial pressure during systole, this can be detected by a pattern analysis of an intracranial pressure wave. Fig. 13A to 13B show a plurality of examples of such effects. Changes in the plurality of patterns may be detected, for example, by using template pairing or by calculating a distance between an existing pattern and a desired pattern. Various methods of aligning patterns and/or detecting pattern changes in one-dimensional signals are known in the art and may be used.

In some exemplary embodiments of the invention, the target function of the therapy may comprise a plurality of different physiological measurements. Optionally, a composite score is comprised of the measurements and the adjusted treatment to result in a physiological state having a score corresponding to (e.g., reaching, exceeding) the score.

At 580, the process of adjusting and using the system 500 is repeated. It should be noted that a user (e.g., a physician) may be alerted, for example, by using lights, sounds, and/or an electronic message if the adjustment fails and/or the patient exceeds multiple safety limits. In some cases, the adjustment is performed manually, and a user may be alerted to process the system and provide input (e.g., carotid Doppler sensing) as part of an adjustment procedure.

In some exemplary embodiments of the invention, instead of looking at an integral value over a period of time, what is seen is a derivative, e.g., a change in flow as a function of time. For example, an increase in this index indicates a functional improvement even if it does not show a change in the intracranial pressure and/or the cerebral blood flow and/or the perfusion. In some exemplary embodiments of the invention, it is noted that the cerebral perfusion pressure may provide a better indicator than the intracranial pressure, which depends on other physiological parameters. Alternatively, the cerebral perfusion pressure is used instead of the intracranial pressure for some or all of the methods described herein. It should be noted that the measures described herein for adjustment can also be used for monitoring of the patient (e.g., displayed to a user or sent to a patient or a hospital information system) even if the adjustment is not implemented.

In some exemplary embodiments of the invention, it is noted that the brain is part of a plurality of feedback cycles. In one example, a change in the cerebral blood flow may cause a change in the blood flow of a carotid artery (or other artery). Optionally, feedback used to adjust the system 500 includes measurements in addition to or instead of actual measurements on the brain as an indication of a positive or negative impact occurring.

Some exemplary temporal considerations

According to some embodiments of the invention, the following are exemplary temporal considerations.

In some exemplary embodiments of the invention, the time is based on an event. Alternatively, the event is an R-wave detected in an electrocardiogram, and the activation time of the system 500 is based on a delay time relative to the R-wave and/or an expected next R-wave. Alternatively, a different event is used, for example, the start of a pressure pulse in the carotid or other artery, optionally an artery near the brain.

In some exemplary embodiments of the invention, the constriction is specifically and preferably set to initiate (e.g., within 10 to 20 milliseconds thereof) an increase in arterial pressure rising in the carotid artery. In a pig model, this was found to be about 50 milliseconds after the R-wave was detected from the electrocardiogram.

In some exemplary embodiments of the invention, once the contracted time is according to the electrocardiogram, the arterial pressure is checked, for example, for a short time and/or over a range of the electrocardiogram pattern. Optionally, the beginning and/or end of the deflation before the pressure increase is checked. Optionally, as a safety feature, if this time is not found, the system is prevented from booting up. Alternatively, instead of using the arterial pressure to detect non-compliance, non-compliance is detected using a time relative to the systolic phase of intracranial pressure.

In some exemplary embodiments of the invention, a safety check is arranged to ensure that the expansion occurs during the diastole and/or when the intracranial pressure is low.

In some exemplary embodiments of the invention, it is desirable that the expansion be as close to the deflation as possible. Optionally, a balloon inflated for a short period of time (e.g., 10 to 100 milliseconds, e.g., 5 to 50 milliseconds, e.g., 3 to 30 milliseconds) is provided to allow for an intracranial fluid in response to the inflation. Optionally, a duration of the inflated state is sufficiently long such that when the deflation occurs, the fluid displaced by the inflation (e.g., cerebrospinal fluid, venous blood) does not compete too much with the incoming arterial blood. For example, at least 20%, 30%, 40%, 60%, 80%, or an intermediate percentage of the increase in flow due to the deflation of the balloon is due to the arterial blood. Optionally, this is monitored and/or assessed using imaging, for example using Magnetic Resonance Imaging (MRI) or using Nuclear medicine (Nuclear medicine) imaging, for example using a suitable Positron Emission Tomography (PET) isotope in blood, or using x-ray imaging by detecting a first contrast of x-ray contrast material. Alternatively, this may be detected by examining the overall results, such as cerebral blood flow.

This has two potential benefits. First, the intracranial pressure at this time point may be the lowest. Second, the balloon expands in as short a time as possible and thus has as little disturbance to the brain as possible.

Fig. 5F shows an exemplary duration between the expansion and the expansion in some embodiments according to the invention. Optionally, the contraction time is set (e.g., to account for variability) before the start of the systolic period, and the expansion time is set after the start of the systolic period, but optionally, as described above, as close as possible to the contraction. Alternatively, the expansion may be initiated after the R-wave is detected.

In some exemplary embodiments of the invention, this result is a very low or very low duty cycle for the balloon, the inflation of which is less than 50%, 30%, 20%, 10% or an intermediate percentage of the cycle (e.g., cardiac or intracranial pressure). In some exemplary embodiments of the invention, a plurality of pulses are provided in one cycle. Optionally, the overall duration of the expansion in a cycle is still within these ranges.

In some exemplary embodiments of the invention, a composite score is optimized, the composite score consisting of both the volume of the balloon and the duration of the inflated state of the balloon, e.g., the product of the two yields. In use, the volume is set as described herein, and the duration of an initial inflation state is set, for example, between 50 and 70 milliseconds. This duration is gradually decreased (and optionally increased in volume) based on an effect on an expected measurement (e.g., cerebral blood flow, integral value of cerebral perfusion pressure, etc.). It will be appreciated that different disease states and/or pressures may indicate a need for different durations of distension. Optionally, the system 500 is preprogrammed with a set of disease conditions (e.g., in memory) and is suggested to be associated with any of the starting point, range, sensed signal, desired result, and/or expected result. Indications by a user (or based on values of various parameters and/or by circuitry responsive to operation of the system 500) may be used to identify a disease state and suggest that one or more parameters be changed and/or sensed.

In some exemplary embodiments of the invention, the contraction is timed within 10 to 50 milliseconds (or less, possibly overlapping the high point) before the systolic high point, and the expansion is timed at the last third of the cardiac cycle (e.g., typically between 150 to 330 milliseconds before the systolic high point).

Fig. 13A shows an example of the effect of a good time sequence on brain conditions in a pig model. As can be seen, the cerebral blood flow was increased after initiation at multiple parameters of volume change of 1.8 ml, contraction 90 milliseconds after R-wave (heart rate-about 75 Beats Per Minute (BPM)), expansion 500 milliseconds after R-wave, and intracranial pressure of 28 mmhg. Also of note is the increase in the downward spike of diastole and the flattening and/or splitting of the intracranial pressure peak. Also of note is a reduction in the intracranial pressure. It should be noted that the duration of the inflated state is obviously about 210 milliseconds.

Fig. 13B shows another example of the effect of a good time sequence on brain conditions in a pig model. As can be seen, after initiation, the cerebral blood flow increases and the intracranial pressure decreases at a number of parameters of 1.8 ml volume change, deflation 90 ms after R-wave, inflation 500 ms after R-wave, and intracranial pressure of 34 mm hg. Also of note is the increase in the downward spike of diastole and the flattening and/or splitting of the intracranial pressure peak.

It should be understood that the use of parameters as a treatment guideline is often a decision made by a caregiver. However, a preset value may be programmed into the system 500.

The effects of a poor timing are shown in fig. 14, in this case, for a (low) volume change of 1.2 ml, deflation at 420 milliseconds and inflation at 650 milliseconds. As can be seen, the peak shape of the intracranial pressure changes, but not significantly decreases. This may be due to the overlap of the expansion and the systolic phase and/or the late onset of the contraction. The FIG. 14B shows a longer time view of the effects of a poor timing. As can be seen, the cerebral blood flow is reduced and the improvement of cerebral perfusion pressure is stopped. This may be due to the overlap of the expansion and the systolic phase and/or the late onset of the contraction.

In some exemplary embodiments of the invention, the plurality of parameters for treating the increase in intracranial pressure comprise: expansion between-400 and +500 milliseconds with respect to the R wave; tightening between-50 and +90 milliseconds with respect to the R wave; the rate of inflation/deflation to reach maximum volume change is between 5 to 300 milliseconds (alternatively 5 to 50 milliseconds) and a volume change of between 1 to 4 milliliters. It should be noted that in some embodiments, rather than the volume of the balloon being controlled, the pressure of the balloon is optionally selected to remain below the peak intracranial pressure. Optionally, during the deflation, a fluid is removed from the balloon based on volume considerations rather than pressure considerations (e.g., removing 2 milliliters of fluid rather than reducing the volume of the balloon to 25 mm hg).

Multiple pulse modes

In some exemplary embodiments of the invention, more than one pulse is provided per cycle. For example, two or more of the pulses are provided. Some examples of the two pulsations include: expansion followed by deflation, followed by expansion followed by deflation; inflation followed by a first deflation and then a second deflation; or expanded, followed by another expansion, and then deflated.

From a functional point of view, the pulsation may be reversed: first deflated and then inflated. Similarly, since the pulses are often applied every cycle, one portion of a pulse may overlap a cycle that is different from another portion of the pulse.

Also, it should be noted that when a pulse (or more than one) is applied in each cycle, in some embodiments, the applied cycles are less than all cycles, e.g., cycles that skip R-waves (or other temporal events that are not correctly detected), cycles that follow some negative or positive indication seen in the feedback (e.g., a decrease in cerebral blood flow), or an overall protocol that defines that the pulse is not applied in each cycle, e.g., every other cycle or using some other sequence. Optionally, the frequency of the plurality of treatment cycles is increased at the beginning of a treatment and/or decreased at the end of a treatment. Optionally, the balloon body is deflated between said pulsing applications. Alternatively, the balloon may be in an inflated state.

In some exemplary embodiments of the invention, the pulse (inflated followed by deflated) is provided to improve systolic rise and an additional pulse is also provided. Optionally, this additional pulsation is provided after the completion of the systolic phase, or at least when most of it is completed, and optionally during the time between the middle and the last third of the diastolic phase. In some exemplary embodiments of the invention, the selection of the time occurs when blood moves to the venous space (and thus cannot assist perfusion) and begins to drain toward the plurality of venous sinuses. It should be noted that the plurality of venous sinuses are progressively unaffected by the intracranial pressure. The additional pulsations may optionally be timed and/or have a volume and/or other parameters to encourage the blood to flow into the venous sinuses, and once constricted, allow the blood to flow (e.g., through arteries) to perfuse the brain.

In one example, the balloon is inflated within a short period of time (e.g., 5 to 50 milliseconds) so as to cause a sudden increase in the intracranial pressure during the diastole such that venous blood is pushed out of the intracranial system, and then the balloon is deflated. Next, a systolic pulsation is optionally applied-a pre-systolic contraction followed by an expansion at the late diastole. The systolic pulsation may include, for example, a duration of an expanded state of 10 to 30 milliseconds.

In some exemplary embodiments of the invention, an inflation/deflation cycle is set to increase diastole to assess venous blood from the brain by using the intracranial pressure to engage venous vasculature-where slightly increasing the intracranial pressure compresses multiple veins but not enough to compress an arterial system. Because the venous sinuses are occluded in strong incompressible spaces, the venous blood can flow out of the body, despite the increased intracranial pressure, but does not collapse at an outlet, but cannot flow back into the brain once it exits the brain because of the high resistance and pressure of the arterial system (and brain). A potentially desirable result is that more volume is available for oxygenating blood flow. Optionally, this determines the volume of this pulsation, which is optionally selected to increase the intracranial pressure (which may be determined during set-up) to, for example, 15 to 25 mm hg or higher, in order to achieve an instantaneous compression of the venous bed (which is opened due to the hard venous sinuses). While in some embodiments the compression will reach the baseline value, in some embodiments the compression will not, it may help prevent venous return.

In some exemplary embodiments of the invention, an additional sensor is used to estimate the effect on venous flow, e.g., during setup and/or use of the system, searching for and adjusting, e.g., optimizing. For example, a sensor that calculates venous pressure as close as possible to the cerebral venous vasculature (e.g., a jugular venous pressure monitor, or a central venous pressure monitor or a direct venous sinus pressure measurement) is provided and its calculated value is used as a marker for selecting pulsation parameters, such as time and volume.

In some embodiments of the invention, the overall duration of the inflation state in all pulses is maintained short, e.g. less than 100 milliseconds, e.g. between 30 and 60 milliseconds, or less.

As described above, the number of pulses and other properties of the pulses may be selected, performed manually and/or automatically during setup and/or on an existing basis.

It should be noted that in some embodiments (e.g., for patients with certain disease states) it may be desirable to always or sometimes omit the systolic pulsation, but maintain the diastolic pulsation, and vice versa.

FIG. 5G illustrates a process of applying two pulses in some embodiments according to the invention.

At 582, a physiological event, such as optionally detecting R-waves and setting various time parameters. In some embodiments, inflation of the balloon is directly controlled by a detected physiologic event and time relative to the event, without predicting future events, such as, for example, if a determination is made from the detection of an R-wave and the time applied for deflation of the balloon.

At 584, the systolic time is optionally determined (e.g., by using a detected R-wave or R-to-R delay time) to calculate when to perform a pre-systolic expansion.

At 586, a first expansion of the balloon is performed.

At 588, a first delay time is initiated in the inflated state while the balloon is maintained inflated.

At 590, the balloon is deflated, e.g., just prior to the systolic phase.

At 592, the diastolic period is optionally determined, optionally by using a sensor for determining the safety of a second expansion and/or simple transit time calculation.

At 594 to 598, the second expansion is applied, optionally by using parameters different from a first pulsation.

Fig. 5H shows the time and expected effect of the second pulsation as a dotted line, while a solid line shows the expected effect of a single pulsation. As can be seen, as the intracranial pressure increases, it need not increase beyond a maximum value during the peak of the intracranial pressure during the systolic phase. Possibly, a last intracranial pressure increase before the systolic phase becomes smaller due to double pulsation. This effect may be useful in addition to or instead of better perfusion effect due to venous compression. Possibly, as shown, the use of the double pulsation will result in an overall reduced intracranial pressure over the majority of the intracranial pressure cycle.

Exemplary devices for influencing cerebral perfusion pressure

Reference is now made to fig. 6, which schematically illustrates an alternative device in the form of an balloon for influencing the cerebral perfusion pressure, according to some embodiments of the present invention.

In some embodiments, a volume adapter is provided in the form of an air sphere 601. In some embodiments, the balloon 601 is included at a distal end of a catheter. Alternatively or additionally, the balloon 601 is included at a distal end of an extra-ventricular drainage device, wherein the distal end is an end within the brain. Alternatively or additionally, the balloon 601 is in fluid communication with at least one tube, optionally a suction tube 668 and/or an inflation tube 666. In some embodiments, the tubing is connected to at least one pump, optionally a pump 648 for the suction tube, and/or a pump 646 for the inflation tube. In some embodiments, the plurality of pumps is a plurality of syringe pumps. Alternatively or additionally, the plurality of pumps have any other form known in the art. In the case where the balloon 601 is filled with ambient air, in some embodiments, only the inflation tube 666 and the pump 646 are provided, and air is allowed to exit the balloon 601 through the setting of a valve.

Optionally, the at least one pump is coupled to at least one motor. Optionally, each of the suction pump 648 and the inflator 646 are in operative communication with the motor 638 and the motor 636, respectively. In some embodiments, the motor 638 and the motor 636 are controlled by a processor.

In some embodiments, a pressure sensor 620 measures an intracranial pressure, and an output of the pressure sensor 620 causes a fluid to stop being pumped into or out of the balloon 601 if the pressure exceeds a predetermined range. In some embodiments, the output of the pressure sensor 620 goes to the same processor in operative communication with the motors 636 and 638.

In some embodiments of the invention, a plurality of intracranial pressure change systems, as referenced above, may be used, after suitable alteration, for example, to allow and provide the temporal and volumetric features described herein, for carrying out some embodiments of the invention.

Also, it should be noted that the description herein focuses on patients with high intracranial pressure. However, other cerebral blood flow problems can be treated by using the systems and methods described herein, for example, diseases such as those described in the above references.

For example, the systems and methods described herein can optionally be used to increase intracranial pressure or cerebral perfusion pressure in any portion of the circulation, flatten intracranial pressure, provide venous compression, improve perfusion, improve outflow, and/or other effects described herein.

Deformable conduit

Fig. 7A shows one embodiment of a volume adapter comprising a conduit 700, the conduit 700 having a resilient and/or deformable portion 702. Optionally, a change in configuration alternates an open or closed configuration of the deformable portion as a way to increase and/or decrease the volume of a brain compartment surrounding the conduit. For example, the deformable portion of the catheter may be deflated into the inner chamber of the catheter to increase the volume of the surrounding compartment and optionally reduce the intracranial pressure. Alternatively or additionally, the deformable portion of the catheter may be expandable to invade the surrounding compartment in order to push into tissue and potentially increase the intracranial pressure.

Fluid propulsion

Figure 7B shows an embodiment in which a fluid is propelled into a conduit 750 by actively rotating a wheel 755, the wheel 755 having a plurality of collecting elements 757, e.g., a paddle configured to resist the fluid as it passes through the paddle. Expelling the fluid entering the catheter from the brain compartment and/or from a balloon disposed in the brain compartment, thereby causing a reduced volume and a reduced intracranial pressure.

Double catheter

FIG. 7C shows an embodiment in which a conduit 710 is provided around a second inner conduit 711, which has a smaller caliber. In some embodiments, the inner conduit contains a fluid that exerts a pressure radially outward proportional to a resistance to outflow. Optionally, the fluid of the inner conduit is changed by a processor having instructions for operating in synchronization with a cardiac cycle.

Referring now to fig. 7D, a configuration of a dual conduit is illustrated in which two conduits (or two chambers, 720a and 720b) are disposed side-by-side according to some embodiments of the present invention. In some embodiments, a ratio between the fluid volumes in each chamber is controlled, optionally by an external pump. In some embodiments, the filling and draining of the chamber is done simultaneously. Alternatively, one chamber is designed for filling with the fluid and the other chamber is designed for draining the chamber.

Skull resection placing film

Fig. 8 shows an embodiment in which a limited craniectomy is performed in the skull 810, followed by a membrane 800 covering at least a portion of a brain compartment. Optionally, the membrane is flexible and/or resilient. In some embodiments, the membrane is controlled by a processor, optionally with instructions to relax and/or compress the membrane to cause it to move in the a or B directions, respectively. In some embodiments, the membrane is relaxed and/or compressed according to a cardiac cycle and/or according to an intracranial pressure synchronized to the cardiac cycle.

Vena sinus balloon

Fig. 9 illustrates a balloon 900 according to some embodiments of the invention, the balloon 900 being provided as a sinus balloon-a balloon at least partially inflated in the sinus 910. In some embodiments, the venous balloon is gated to an electrocardiogram, optionally inducing a momentary increase and/or decrease in venous pressure, potentially resulting in a resistance to outflow, optionally a gradual resistance.

Volume pressure curve

In some exemplary embodiments of the invention, use consists of the ability to coordinate a change in fluid volume with a cycle of intracranial pressure. In one example, a pressure-volume curve is generated by injecting the fluid (into the brain or, for example, into a balloon sealed against the brain) at known points in time during the cycle. Optionally or alternatively, a plurality of known fluid volumes are removed (or deflated) at a plurality of known points in time of the cycle. In particular, it should be noted that time can be coordinated to multiple extremes of the cycle-a peak of systolic phase and a trough of diastolic phase.

Fig. 10 is a method of determining a volume-pressure curve according to some embodiments of the invention.

At 1002, a point in the cardiac cycle is selected, optionally at the end of a diastole when the brain is maximally drained of blood.

At 1004, a volume amount (volume difference, Δ V) to be injected is selected, for example, 0.1 ml.

At 1006, the volume difference is injected, for example, by expanding the adaptor 101 by a test amount, for example, relative to a previous activation or relative to a non-expanded baseline.

At 1008, the effect of, for example, the injection on an intracranial pressure and/or other physiological parameter is detected.

At 1010, the brain is optionally allowed to stabilize at a new set point.

At 1012, the volume difference is increased, for example, at a fixed spacing of 0.1 ml, and the process is repeated.

At 1014, the brain response is gathered to define a pressure-volume function, which may also be used to indicate compliance of a brain. Alternatively, the process may be repeated at other stages of the cardiac cycle, for example, to achieve the compliance under different blood-volume conditions.

In some exemplary embodiments of the invention, determining a compliance curve may be useful for calculating the compliance, pressure/volume differences (dP/dV) may be calculated and a state of brain reserve and/or a point of decompensation may be evaluated. This may help to differentiate between different disease states, for example, a patient with normal stress but reduced reserves may be at higher risk and may require more aggressive treatment than a patient with greater stress but greater reserves. This may also affect suggested treatment parameters, seek start parameters, and/or markers for evaluating treatment.

Fig. 11 shows an exemplary pressure-volume curve. In this figure, a 0 point (e.g., the trough of diastole, where the brain is most relaxed) is known accurately and consistently across multiple cycles. The same av (e.g., between 0.01 ml and 1 ml, e.g., between 0.05 and 5 ml) is injected at the same precise point of the pressure-volume curve to produce 0 to 5 points in the graph, so an operator or system can reconstruct a pressure-volume curve (dashed line) based on a simultaneously measured intracranial pressure.

General rule

It is expected that during the life of a patent maturing from this application many relevant injector devices will be developed and the scope of the term injector and/or cartridge is intended to include all such new technologies as have been translated.

The term "about" as used herein means ± 25%.

The various terms "comprising", "including", "having" and their equivalents mean "including but not limited to".

The term "consisting" means "including but not limited to".

The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and/or components, but only if the additional ingredients, steps, and/or components do not materially alter the basic and novel characteristics of the composition, method, or structure as claimed.

As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in form of the ranges is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, a range description such as from 1 to 6 should be considered to have specifically disclosed various sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as various individual values within that range, e.g., 1, 2, 3, 4, 5, and 6. These apply regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any number (decimal or integer) recited within the indicated range. The phrases "ranging/ranges between …" ("ranging/ranges between") are a first indicating number and a second indicating number and "ranging/ranges from" a first indicating number "to" a second indicating number are used interchangeably herein and are meant to include the first indicating number and the second indicating number as well as all fractional and integer numbers therebetween.

As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a particular task including, but not limited to, those manners, means, techniques and procedures either known or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiments are inoperable without those elements.

While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents, and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. They should not be construed as necessarily limiting the scope of the chapter headings used.