Patent Description:
Embodiments described in this application may be used in combination or conjunction, or otherwise, with the subject matter described in one or more of the following:.

Managing inflammation in neurocritical care is often desirable. There are a number of indications that could benefit from cooling, including spinal cord injury, traumatic brain injury, head trauma, cerebral ischemia, seizures, fever, thoraco-abdominal aortic aneurysms (TAAA), hydrocephalus, cerebrospinal fluid (CSF) leaks, aneurysmal subarachnoid hemorrhage, and others.

Fever occurs in <NUM>-<NUM>% of critically ill neurologic patients and may adversely affect neurologic outcome. Specifically, fever occurs in up to <NUM>% of patients with ischemic stroke and intracerebral hemorrhage and in <NUM>-<NUM>% of patients with severe traumatic brain injury or aneurysmal subarachnoid hemorrhage. Fever is independently associated with increased morbidity and mortality after ischemic and hemorrhagic stroke. In subarachnoid hemorrhage and traumatic brain injury patients, temperature elevation has been linked with increased intracranial pressure.

Regarding spinal cord injury, although significant damage is caused by the mechanics of the traumatic spinal cord injury, secondary injury that follows is often even more dangerous. It occurs within the first <NUM>-<NUM> hours following the injury and can last up to <NUM>-<NUM> days, depending on the severity of the injury. Secondary injury causes physiological disturbances that disrupt the body's homeostasis, such as initiating a cellular inflammatory response at the injury site and increasing the release of free radicals. An overabundance of free radicals contributes to tissue ischemia, cerebral edema, and disruption of the spine-blood barrier. The use of hypothermia as a therapeutic agent has been shown effective in providing neuroprotection from secondary injury. Research has shown the benefits of hypothermia include decreasing oxygen consumption, free radical generation, neurotransmitter release, inflammation, and metabolic demands. Even a temperature decrease of <NUM>-<NUM> can be beneficial at the cellular level.

As disease awareness and diagnostic modalities continue to improve, the prevalence of thoracic and thoracoabdominal aortic aneurysm (TAAA and dissection) is increasing, affecting up to <NUM> individuals per <NUM>,<NUM> per year. Paraplegia remains one of the most devastating complications of thoracoabdominal aortic surgery, and is associated with a significant increase in both morbidity and mortality. Both pharmacological and mechanical modalities used to control central hypertension during aortic occlusion affect CSF dynamics and spinal cord perfusion pressure. Although lumbar drainage has been successfully used for TAAA patients for over <NUM> years, their introduction to TAAA as standard of care has been slow to evolve. In fact, lumbar drainage has cut the rate of paraplegia from <NUM>% to <NUM>-<NUM>% and the growth of minimally invasive TEVAR procedures has meant that the rate is now conservatively estimated at about <NUM>-<NUM>%. This still means that approximately <NUM>,<NUM> people die or experience permanent weakness and disability each year. The two main approaches to protect the spinal cord during TAAA repair include maximizing spinal cord perfusion and inducting systemic hypothermia. Regional hypothermia may have fewer side effects, but epidural cooling can cause a sharp increase in CSF pressure and attenuate spinal cord perfusion.

Traumatic brain injury is a major source of death and severe disability worldwide. In the United States alone, <NUM> million people suffer a traumatic brain injury each year. Approximately <NUM>,<NUM> people die and <NUM>,<NUM> remain permanently disabled. Therapeutic hypothermia can be an effective intervention to reduce intracranial pressure and protect against secondary ischemic neuronal injury. Despite its therapeutic benefit, systemic hypothermia is associated with many potential side effects that have limited its widespread use including depth of cooling, coagulopathies, shivering, arrhythmias, and immune suppression, with increased susceptibility to infection and electrolyte imbalance. Furthermore, following a traumatic brain injury, a variety of inflammatory cytokines (e.g. IL-<NUM>, IL-<NUM>, and TNF) have been shown to worsen neuroinflammation, contribute to secondary brain damage and worse long-term outcomes.

Current methods for cooling include inducing systemic hypothermia in a patient, the use of cooling helmets, cooling the patient's blood, and circulating coolant through a closed loop within the CSF space. Typical ranges of systemic hypothermia include <NUM> to <NUM>. There are several reasons why hypothermia is challenging to implement clinically despite its benefits. Current hypothermia methods can cause serious adverse events, such as arrhythmias, infection, sepsis, coagulopathy, electrolyte abnormalities, mild acidosis, a rise in lactate levels/amylase levels, excessive localized cooling or necrosis, skin issues, and other issues. Accordingly, there is a need in the art to provide cooling without the risks of current methods.

<CIT> discloses an apparatus and method for uniform selective cerebral hypothermia. The apparatus includes a brain-cooling probe, a head-cooling cap, a body-heating device and a control console. The brain-cooling probe cools the cerebrospinal fluid within one or more brain ventricles. The brain-cooling probe withdraws a small amount of cerebrospinal fluid from a ventricle into a cooling chamber located ex-vivo in close proximity to the head. After the cerebrospinal fluid is cooled it is then reintroduced back into the ventricle. This process is repeated in a cyclical or continuous manner. The head-cooling cap cools the cranium and therefore cools surface of the brain.

<CIT> relates to methods and apparatus for accomplishing the closed recirculation of cerebrospinal fluid (CSF), typically synthetic in nature, through the cerebral and spinal regions of the body and the replenishment and revitalization equipment. A preferred cassette variation includes a modular disposable package of equipment preferably packaged in such a way that it is readily and quickly employed in an emergency.

The subject-matter of the present invention is defined by the features of the independent claim. Certain embodiments may provide focal cooling at a treatment site of a human or animal subject by deploying a multi-lumen catheter (i.e., a catheter with two or more lumens) near the treatment site. CSF may be withdrawn from near the treatment site through an inlet lumen of the catheter. The withdrawn CSF may be chilled and then returned through an outlet lumen of the catheter. A characteristic of the treatment site may be measured using a sensor and then compared against a treatment target. The comparison may then be used to modify a treatment parameter.

Certain embodiments may provide focal cooling at a treatment site of a human or animal subject by deploying a multi-lumen catheter near the treatment site. CSF may be withdrawn or drained from near the treatment site through an inlet lumen of the catheter. A heat transfer fluid may be circulated through a cooling lumen of the catheter. A characteristic of the treatment site may be measured by a sensor. The measured characteristic may be compared with a treatment target and used to modify a treatment parameter.

Certain embodiments may provide focal cooling at a treatment site of a subject by cooling the treatment site until a first treatment target is reached, maintaining a temperature at the treatment site until a second treatment target is reached, and enabling the treatment site to reach a third treatment target. As used herein, references to a "temperature" are understood to refer to a desired temperature range, as appropriate. The first treatment target may comprise a first temperature and a first period of time. The second treatment target may comprise a first temperature and a second period of time. The third treatment target comprising a third period of time and a second temperature that is higher than the first temperature.

Disclosed embodiments generally relate to systems and methods for focal cooling of the brain and spinal cord of a human or animal subject; however, applications may extend beyond focal cooling of these regions to other anatomical locations and other temperature modification (e.g., normothermia or focal warming). Some embodiments may provide selective spinal cord cooling, pressure monitoring and automated drainage. Such embodiments may include a multi-lumen catheter, a drainage collection reservoir bag, a pump to circulate fluid, sensor hardware and controllers. Embodiments may modulate the flow of the circulating fluid for cooling to modulate therapeutic hypothermia and re-warming. Embodiments may enable local hypothermic neuroprotection, limit the stress of cooling, minimize secondary neuronal damage and achieve neuroprotection while improving workflow as a result of automated drainage. Disclosed focal cooling methods may enable cooling to about <NUM> or about <NUM>, below safe ranges for present techniques, including for systemic hypothermia. In addition, focal spinal cooling may trigger a cascade of neuroprotective reactions that have an overall beneficial setpoint control effect. Accordingly, focalized cooling techniques disclosed here may be even more neuroprotective than traditional systemic hypothermic techniques. Cooling of <NUM> below normal internal human body temperature (approximately <NUM>) may benefit a patient and may amount to an approximately <NUM>% decreased metabolic rate.

Another advantage is that the disclosed systems and methods allow for rapid cooling and rapid rewarming. Inflammation and temperature control occurs in the brain, so the focus on thermoregulatory centers versus indirect cooling in blood provides improved patient outcomes.

Disclosed embodiments may also be used to minimize inflammation in neurocritical care. In particular, cytokine filtration combined with drainage and cooling of CSF may provide a potent rapid therapy that improves outcomes in multiple disease states. Decreasing the cytotox load by approximately <NUM>% and cooling the brain to between about <NUM> to <NUM> may be highly beneficial in severe manifestations of the aforementioned indications.

In certain embodiments, CSF is withdrawn from the spine, cooled, and returned. Certain embodiments may provide cooling using catheters with any suitable number of lumens, such as one or more single-lumen catheters inserted into the subject at one or more locations, a dual-lumen catheter, a tri-lumen catheter with a drainage lumen, or other catheter configurations. Certain embodiments may be configured with a set-it-and-forget-it configuration such that the CSF is withdrawn and temperature controlled using a feedback control system. Certain embodiments may take the form of a lumbar drain having a lumen to circulate a heat transfer fluid.

In certain embodiments, a catheter may be configured for use in cerebral ventricles. In addition, a ventricular cooling catheter that can cool and aspirate may provide benefits in subarachnoid hemorrhage, fever control, seizure control, intracerebral hemorrhage evacuation, traumatic brain injury recovery, and other treatments. A ventricular catheter may enable cooling that is rapid, uniform, and targeted. Embodiments of catheters for use in the cerebral ventricles may be similar to or the same as catheters used in the spine. Certain embodiments may be configured to take into account and overcome the natural warming of the brain and spinal cord by the body. The body typically produces approximately <NUM> to <NUM> of CSF per day. The system may be configured to treat any suitable amount of CSF per hour, such as approximately <NUM> of CSF per hour. The system may be configured to treat approximately <NUM> per hour. Warm blood (about <NUM>) may arrive at the brain at a rate of approximately <NUM> an hour. The treatment flow rate of CSF may be configured to match that rate. In certain embodiments, the flow rate of CSF may be configured to exceed that rate. For example, a flow rate of <NUM> to <NUM> per hour may be used.

Embodiments may provide significant cost-saving workflows in intensive care units and operating rooms as a result of automation compared to gravity-based manual drainage systems. As a result of closed-loop sensing and control provided by some embodiments, intracranial pressure may be controlled using sensors to monitor and maintain a neuroprotective state. Cooling algorithms to maintain and modulate mild-moderate and deep localized hypothermia for up to <NUM> hours or more may be utilized.

<FIG> illustrates an embodiment of a system <NUM> for treating biologic fluids or systems, including a subject <NUM>, a treatment site <NUM>, tubing <NUM>, treatment unit <NUM>, and port <NUM>.

The subject <NUM> may be a human or animal subject undergoing treatment. The subject may have a treatment site <NUM>. The treatment site <NUM> may be a location at or to which therapy is applied, but the treatment site <NUM> may, but need not be, the ultimate target of treatment. For example, in a particular treatment, the target tissue may be brain tissue, but it may be treated indirectly by cooling CSF introduced in the spinal region. As another example, brain tissue may be the treatment target and be treated by the application of a cooling balloon against brain tissue in cerebral ventricles of the subject <NUM>. In certain embodiments, the treatment site <NUM> may be a CSF-containing space. The treatment site <NUM> may be a source of a fluid, a destination of a fluid (e.g., CSF), or both. For example, the system <NUM> may remove or receive a volume of fluid from the treatment site <NUM>, perform cooling, filtration, and/or other treatment, and return a portion of the processed and/or treated fluid to the treatment site <NUM>.

The connection between the system <NUM> and the treatment site <NUM> may be made in a variety of ways. For example, the connection with the treatment site <NUM> from system <NUM> may be made through one or more catheters inserted into particular anatomical locations. For example, the catheter may be a multi-lumen catheter inserted through a single opening in the subject to access the anatomical location, or may be two catheters inserted at different but connected anatomical locations.

The various components of the system <NUM> may be connected through tubing <NUM>. For instance, in certain embodiments, there may be a length of the tubing <NUM> placing the treatment site <NUM> in fluid connection with the port <NUM>. The tubing <NUM> may be any suitable material or system for transporting or containing fluid. While the connections of the system <NUM> are shown as being direct, the connections need not be. The various portions of the system <NUM> may be connected through combinations of connections and various tubing <NUM>. In certain embodiments, the tubing <NUM> and other portions of the system <NUM> may be filled with priming fluid (e.g., saline). Longer lengths of tubing <NUM> may correspondingly comprise a larger amount of priming fluid; however, in certain implementations, larger amounts of priming fluid may result in an undesirable amount of dilution of "natural" fluid, such as CSF. Accordingly, in certain implementations, the tubing <NUM> may be selected in order to minimize the volume of priming fluid needed, while still having the system be practically useful (e.g., enough tubing to enable the system <NUM> to be used at a subject's bedside). Depending on the subject and the treatment site <NUM>, the tolerance for removal or dilution of fluid may vary, and the system <NUM> may be scaled accordingly. For example, the parameters of the system <NUM> may be changed to scale to suit subjects ranging from a mouse to a human or larger mammals.

In certain embodiments, the tubing <NUM> may be insulated to decrease warming of fluid (e.g., heat transfer fluid and/or CSF) as it travels through the tubing <NUM>. In certain embodiments, the tubing may be placed within an ice bath or other cooling source to cool the fluid in addition to or instead of using the temperature control unit <NUM> of the treatment unit <NUM>. In certain embodiments, the tubing <NUM> may be comprise a jacket that surrounds the tubing <NUM>. The jacket may be insulated to limit temperature changes in the fluid passing through the tubing. The jacket may also be configured to modify the temperature of the fluid. For example, the jacket may comprise coils through which warmed or cooled liquid may flow in order to modify the temperature of the tubing and the fluid flowing therein.

The treatment unit <NUM> may be a device or combination of devices configured to cool or otherwise treat fluid received through the port <NUM>. The treatment unit <NUM> may be further configured in accordance with the disclosures herein (see, e.g., <FIG>).

The port <NUM> may be a port through which fluid enters and exits the treatment unit <NUM>. The port <NUM> may be any kind of port through which material or fluid may flow. The port <NUM> may be configured to be in fluid connection with the treatment site <NUM> using the tubing <NUM>. The port <NUM> may include various fittings to facilitate the connection, including but not limited to compression fittings, flare fittings, bite fittings, quick connection fittings, Luer-type fittings, threaded fittings, and other components configured to enable fluid or other connection between two or more components. In addition to fittings, the port <NUM> may also include various elements to facilitate use of the system <NUM>, including but not limited to various valves, flow regulators, adapters, converters, stopcocks, reducers, and other elements. In certain embodiments, there may be two or more ports <NUM>. This configuration may facilitate the use of different systems with the treatment unit <NUM>.

<FIG> illustrates a block diagram of a treatment unit <NUM>, according to certain embodiments, with solid connections indicating example fluid flow connections for fluids and materials, and dashed connections indicating signal connections for the flow of signals and information. The treatment unit <NUM> may comprise the port <NUM>, a temperature control unit <NUM>, a filter <NUM>, a sensor <NUM>, a pump <NUM>, a processing unit <NUM>, and an interface <NUM>.

The temperature control unit <NUM> may be a unit configured to cool fluid (or heat it, as needed to reach a desired temperature for the subject). Various techniques may be used depending on the fluid and the desired results, including but not limited to vapor-compression, thermoelectric cooling, radiator, other techniques, or combinations thereof. In certain embodiments, the fluid is CSF or other liquid removed from the subject <NUM> that will later be returned to the subject <NUM>. In other embodiments, the fluid is a heat transfer fluid that may be circulated to cool the fluid or the treatment site. Certain embodiments may be configured to provide cooling for both biologic fluid and heat transfer fluid.

The filter <NUM> may be a device for separating a first portion of materials and/or fluid from a second portion of materials and/or fluid. The design and type of the filter <NUM> may vary depending on the type of fluid and the desired filtration results. Various kinds or combinations of filters may be used to achieve different kinds of filtration. For example, the filters may include filters of various pore sizes and different attributes, such as ultrafiltration, microfiltration, macrofiltration and other sized filters that have various porosities. Combinations of filters may include dead end filtration, depth filtration, tangential flow filtration, affinity filtration, centrifugal filtration, vacuum filtration, and/or combinations thereof. In an embodiment, the filter may be configured to filter cytokines. Examples of cytokines and other proteins that may be filtered may include, but need to be limited to, EGF, Eotaxin, E-selectin, fas ligand, FGF2, Flt3 lig, fractalkine, G-CSF, GM-CSF, GRO, ICAM, IFNa2, IFNg, IL10, IL12p40, IL12p70, IL13, IL15, IL17, IL1a, IL1b, IL1ra, IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL9, integrins, IP10, L-selectin, MCP1, MCP3, MDC, MIP1a, MIP1b, PDGF-AA, PDGF-AAAB, P-selectin, RANTES, sCD40L, sIL2R, TGFa, TNF, TNFb, VCAM, VEGF, and others. In some embodiments, the filter may be configured to capture and absorb cytokines in the about <NUM> to about <NUM> kDa range where most cytokines reside. The sensor <NUM> may be a device for generating and/or receiving information. In certain embodiments, the sensor <NUM> may receive or generate information regarding characteristics of the fluid withdrawn from the treatment site <NUM>, before, after, and/or during treatment. The characteristics may include, for example, temperature, pressure, the fluid flow rate to the treatment site <NUM>, fluid flow rate from the treatment site <NUM>, an amount of contaminants in the fluid, a type of contaminants in the fluid, other measurements of the fluid, and/or combinations thereof. The sensor <NUM> may be configured to generate or receive information regarding components of the system <NUM>, such as a status of the temperature control unit <NUM>, an efficiency rating of the temperature control unit <NUM>, a status of the filter <NUM>, an efficiency rating of the filter <NUM>, a status of the pump <NUM>, an efficiency rating of the pump <NUM>, and an indication of clogs within the system. While the sensor <NUM> is shown within the treatment unit <NUM>, one or more sensors <NUM> may be located elsewhere in the system <NUM> and/or cooperate with other locations. For example, the sensor <NUM> may include sensors configured to take readings from the subject <NUM>. The sensor <NUM> may convert the data into computer- and/or human-readable representations for processing and review. While a single sensor is shown within the system <NUM>, it will be understood that there need not be only as single sensor. Any suitable number of sensors may be used for taking one or more readings throughout the system.

In some embodiments, the sensor <NUM> may be selected to or optimized for use with flow rates of approximately <NUM> to approximately <NUM> milliliters per hour, volumes of approximately <NUM> to approximately <NUM> cubic centimeters, and pressures of approximately <NUM> to approximately <NUM> mmHg. These measurement ranges may be encountered in the system, such as in the flow rate, volume, and pressure of CSF or a heat exchange fluid. In some embodiments, the flow sensor may be accurate within a range of between approximately <NUM> to approximately <NUM> milliliters per hour, the pressure sensor may have an effective operating range of between approximately -<NUM> mmHg and approximately <NUM> mmHg. In some embodiments, sensor <NUM> may have a response time of approximately <NUM>. In some embodiments, the sensor <NUM> may be a temperature sensor configured to have an accuracy of +/- <NUM>. <NUM> between approximately <NUM> and approximately <NUM>. Suitable sensors may include flow sensors provided by SENSIRION of Switzerland, pressure sensors by UTAH MEDICAL of Midvale, Utah, and temperature sensors by SCILOG of Madison, Wisconsin.

The pump <NUM> may be any device for inducing fluid flow through one or more portions of the treatment unit <NUM>. In certain embodiments, the pump <NUM> may be a peristaltic pump, which may reduce the need for sterilization of complex pump components; however, other types of pumps may be used. The operation of the pump <NUM> may be controlled by modifying the operating parameters of the pump <NUM>. This may enable the flow rate, pressure, and/or other parameters of the pump <NUM> to be changed. The pump <NUM> may also be used to withdraw the fluid from and/or return fluid to the treatment site <NUM>. In certain embodiments having multi-lumen catheters, there may be one pump per lumen.

The processing unit <NUM> may be a device configured to control the operation of the treatment unit <NUM>, for example by sending signals to the temperature control unit <NUM>, filter <NUM>, sensor <NUM>, and/or pump <NUM>. In some embodiments, the signals are sent in response to input from the interface <NUM>. In certain embodiments, the processing unit <NUM> may be processing information, such as data received from the sensor <NUM> and/or the interface <NUM>, and making decisions based on the information. In certain embodiments, the processing unit <NUM> may itself make decisions based on the information. For example, the processing unit <NUM> may include a processor and memory for running instructions configured to receive input, make decisions, and provide output. The processing unit <NUM> may be further configured to receive and log data or results from the various sensors of the system <NUM>.

The interface <NUM> may be a device or system of devices configured to receive input and/or provide output. In certain embodiments, the interface <NUM> is a keyboard, touchpad, subject monitoring device, and/or other device configured to receive input. For example, a healthcare professional may use the interface <NUM> to start or stop the system <NUM> and to modify system parameters, such as the absolute duration of the procedure, pump speed, and other parameters. The interface <NUM> may also include a display, speaker, or other device for sending user-detectable signals. In certain implementations, the interface <NUM> may comprise a network interface configured to send communications to other devices. For example, the interface <NUM> may enable the treatment unit <NUM> to communicate with other cooling systems, filtration systems, flow control devices, a server, and/or other devices.

The system <NUM> and/or the treatment unit <NUM> may comprise various flow regulators and sensors to facilitate or otherwise control flow of fluid throughout the system <NUM>. The flow regulators may be devices configured to regulate one or more fluid flow characteristics of the system <NUM>. These characteristics may include but are not limited to flow rate, direction, and pressure. The flow regulator may include various components or subsystems for controlling flow characteristics and may include pressure regulators, backpressure regulators, sensors, and/or other devices. The flow regulators may be controllable by other components of the system (e.g., processing unit <NUM>).

<FIG> illustrates a multi-catheter system for treating fluid near a treatment site <NUM>. A first catheter <NUM> may be located at a first location and a second catheter <NUM> may be located at a second location. The first and second locations may be in fluid connection (e.g., two different portions of a CSF-containing space). A first catheter <NUM> may be deployed in a portion of a CSF-containing space that is more cranial than the location of the second catheter <NUM>. For example, the first catheter <NUM> and the second catheter <NUM> may be inserted a distance of more than one vertebrae apart. In some embodiments, the first catheter <NUM> and/or ports <NUM> thereof may be located near or within the brain of the subject <NUM> (e.g., in a cerebral ventricle), in a lumbar region of the spine, in a cervical region of the spine, and/or in other suitable locations. As illustrated, the second catheter <NUM> is inserted into a CSF-containing space of a spinal portion <NUM>, including vertebrae <NUM>. As illustrated, the first catheter <NUM> has a plurality of ports <NUM> for returning the fluid <NUM>, and the second catheter <NUM> has a plurality of ports <NUM> for withdrawing the fluid <NUM>; however, their roles may be reversed even during treatment (e.g., the first catheter <NUM> withdraws the fluid <NUM> and the second catheter <NUM> returns the fluid <NUM>).

While the catheters <NUM> are illustrated as entering in two different regions (e.g., through two different surgical sites), they need not be so configured. In some embodiments, two catheters <NUM>, <NUM> may be inserted through a single surgical site and one of the catheters <NUM>, <NUM> may be advanced a distance away from the other catheter <NUM>. In addition, the catheters <NUM>, <NUM> are illustrated as single-lumen catheters, but they need not be. The catheters <NUM>, <NUM> may have multiple lumens. In addition, the catheters <NUM>, <NUM> need not have ports <NUM>. Instead, for example, the catheters <NUM>, <NUM> may include a lumen for circulating heat transfer fluid in order to cool or warm the fluid <NUM> and/or the treatment site <NUM>. While the catheters <NUM>, <NUM> are illustrated as having a plurality of ports <NUM>, there may be only a single port <NUM> in some embodiments. In addition, the ports <NUM> may be arranged in various configurations on or along the catheter <NUM>.

<FIG> illustrates a system and method for treating fluid of a treatment site <NUM> in a spinal region <NUM>, according to certain implementations. The certain implementations may include a portion of a spine <NUM> of the subject <NUM>, including vertebrae <NUM>, carrying a fluid <NUM> (for example, a fluid comprising CSF), and a multi-lumen catheter <NUM>. The multi-lumen catheter <NUM> may comprise a first port or first plurality of ports <NUM> and a second port or second plurality of ports <NUM> that place the treatment site <NUM> in fluid connection with tubing <NUM>. As illustrated, a first volume of the fluid <NUM> enters the multi-lumen catheter <NUM> through the first port <NUM> and is passed through into a portion of the tubing <NUM> (for example, a portion of tubing <NUM> leading to the port <NUM>). A second volume of fluid <NUM> enters the multi-lumen catheter <NUM> from a portion of the tubing <NUM> and exits the multi-lumen catheter <NUM> through the second plurality of ports <NUM>.

<FIG> illustrates a system and method for treating cerebral ventricles, according to certain implementations. In this particular example, the catheter <NUM> is placed in fluid connection with the ventricles of a subject's brain <NUM> in a configuration typically referred to as an external ventricular drain. In some examples, a system can be configured to cool more than one ventricle at a time, such as by placing a catheter in more than one ventricle or using multiple catheters for the ventricles. In certain implementations, the connection may be made via an external ventricular drain system.

For example, the tip of a catheter may be placed in a lateral ventricle of the brain. Although <FIG> illustrate accessing CSF in a portion of the spine <NUM> or a portion of the brain <NUM>, the embodiments disclosed herein need not be limited to those regions or that fluid. Embodiments may be used with other fluids, locations, or combinations of locations (e.g., a catheter located in a cerebral ventricle and another catheter located in a portion of the subarachnoid space). For example, one or more single-lumen catheters may be used to transport the fluid <NUM>. Further, cooling need not be limited to one cooling circuit. For example, there can be more than one cooling circuit between the subarachnoid space and the ventricles. As another example, the anatomical location may be a blood vessel and the fluid may be blood.

In certain embodiments, the catheter <NUM> may include one or more lumens. The catheter <NUM> may, but need not, also include ports to place one or more lumens in fluid connection with the fluid <NUM> of the treatment site <NUM>. The catheter <NUM> may be generally configured to be flexible, navigable, and atraumatic. The catheter <NUM> may enable sensing of temperature, intracranial pressure, and/or other parameters. The size of the catheter <NUM> may be approximately greater than or equal to <NUM> French and approximately <NUM> to approximately <NUM> to enable attachment to remote tubing (e.g. the tubing <NUM>), a console (e.g., the treatment unit <NUM>), or other units; however, other sizes may be used. In some embodiments, the catheter size may be approximately <NUM> French.

Temperature control lumen. In certain embodiments, the catheter <NUM> may include a temperature control lumen. The temperature control lumen may be one or more lumens for circulating heat transfer fluid and be configured to cool fluid flowing through a different lumen of the catheter (e.g., an inlet or outlet lumen adjacent to the temperature control lumen), to modify the temperature of fluid flowing external to the catheter (e.g., CSF flowing through the treatment site <NUM>), or a combination thereof. The temperature control lumens may contain multiple flow paths or channels to facilitate the circulation of heat transfer fluid within the temperature control lumen. In certain implementations, the temperature control lumen may extend substantially down the catheter <NUM> and then double back and return to facilitate the inflow and outflow of the heat transfer fluid. In certain embodiments, the heat transfer fluid may extend down the catheter and end in a dead end. The lumen may be scalloped or have structures to increase the surface area and increase or decrease temperature control ability. For example, the internal surface of the temperature control lumen may have internal fins, ridges, or other structures to encourage the exchange of heat from the heat transfer fluid to, for example, the fluid surrounding the catheter.

Inlet and outlet lumens. In certain embodiments, the catheter <NUM> may be configured with one or more inlet and/or outlet lumens. These lumens may be configured for the inflow and outflow of fluid <NUM> and, as such, may be in fluid connection with the fluid of the treatment site <NUM> through openings in the catheter <NUM>. In certain embodiments, the catheter <NUM> need not have both inlet and outlet lumens. For example, a catheter maybe configured for draining fluid <NUM> only, and may have only an outlet lumen. As another example, a catheter configured only for adding fluid <NUM> may have only an inlet lumen. <FIG> illustrates a cross section of an example embodiment of a catheter <NUM> having an inlet lumen <NUM>, a temperature control lumen <NUM>, and an outlet lumen <NUM>. As illustrated, the temperature control lumen <NUM> is disposed between the inlet lumen <NUM> and the outlet lumen <NUM>. In addition, the temperature control lumen <NUM> may have a relatively larger surface area than the inlet lumen <NUM> and the outlet lumen <NUM>.

<FIG> illustrates a cross section of an example embodiment of a catheter <NUM> having an inlet lumen <NUM>, four temperature control lumens <NUM>, and an outlet lumen <NUM>. The temperature control lumens <NUM> are located near the periphery of the catheter <NUM>. These lumens <NUM> may be place in fluid connection with a balloon or other external features of the catheter <NUM>.

<FIG> illustrate an embodiment of a catheter <NUM> having a stylet to provide rigidity. <FIG> illustrates a cross section of the catheter <NUM>, including temperature control lumens <NUM>. <FIG> illustrates the catheter <NUM> with an inserted stylet <NUM>. <FIG> illustrates the catheter <NUM> in a coiled configuration following the removal of the stylet <NUM>. The catheter <NUM> may be constructed so as to form a substantially coiled, twisted, or otherwise distorted shape if a stylet <NUM> is not present within the catheter.

Increased surface area. In certain embodiments, the catheter may be configured to have an increased surface area to facilitate temperature control. The increased surface area may be created by the catheter having scalloped, bumpy, or otherwise inconsistent or complicated external shapes to provide additional surface area.

Heat transfer fluid. Various heat transfer fluids may be used, such as saline or perfluorocarbons. In certain embodiments, different heat transfer fluids may be used at different portions of the temperature control process. For example, the temperature control process may begin with saline as the primary heat transfer fluid and then, after a period of time, use of the saline is discontinued and perfluorocarbons and/or other materials are used. Alternatively, mixtures of fluids may be used, with such mixtures remaining constant and/or changing during the process.

Mixing elements. In certain embodiments, there may be elements or features of the catheter to facilitate mixing of the returning fluid in order to promote mixing of the cooled, returned fluid and the fluid still in the treatment site <NUM>. The elements that enhance mixing can be external or internal to the body of the subject <NUM>. In one example, the catheter <NUM> may include a helical or double helical design to create disruption and turbulence of passive CSF flow and more mixing and exchange of endogenous for processed CSF. Other examples include the creation of eddies or turbulence to enhance mixing through the use of jets or directed outflow. In other examples, small fins, nonplanar surfaces, ribbed portions, balloons, and/or other systems, such as along or within the length of the catheter <NUM>, may promote mixing and/or exchange of endogenous and processed CSF.

Catheter materials. The catheter or portions thereof may be configured to utilize particular materials in order to encourage or discourage particular effects. For example, materials may be selected to encourage or discourage heat transfer to particular regions of the catheter. In particular, with reference to <FIG>, there may be insulation disposed to limit cooling of the inlet lumen <NUM> by the temperature control lumens <NUM>. This may be advantageous because the fluid in the inlet lumen <NUM> is leaving the body and cooling that fluid may have little effect on the temperature of the treatment site <NUM>. Conversely, the outlet lumen <NUM> may lack insulation or be configured to encourage the fluid in the outlet lumen <NUM> to be cooled by the heat transfer fluid flowing through the temperature control lumen <NUM>. Similarly, there may be materials to move the heat towards or away from an exterior of the catheter.

Infection mitigation. The catheter <NUM>, tubing <NUM>, and other portions of the system <NUM> may be configured to reduce the likelihood of infection or contamination of the treatment site <NUM>. For example, the catheter's material may coated with protein-repellant coatings, microorganism-repellant coatings, antibiotic coatings, and/or coatings containing silver (e.g., silver nanoparticles) to discourage infection. As another example, protective sealants may be added to the brain. In some embodiments, anti-microbial components (e.g., washers) may be added to attachment points within the system in order to provide enhanced infection control.

<FIG> illustrate embodiments that include temperature control balloons.

Temperature control balloons may be configured to be placed in contact with a wall of the lateral ventricle. The temperature control balloons may modify temperature by circulating heat transfer fluid in an expandable portion touching tissue near the treatment site <NUM> to cool the brain parenchyma, spinal cord, or other target. When utilized in a cerebral ventricle, the inflation of the balloon may displace CSF in the ventricles.

<FIG> illustrates an embodiment of a catheter <NUM> having a temperature control balloon <NUM>. Disposed in or on the balloon are pathways <NUM> through which heat transfer fluid may flow. The balloon may be expanded by filling it with air, fluid, or via other means.

In addition to the pathways <NUM>, there is a lumen <NUM> extending through the balloon.

The lumen <NUM> may carry CSF, heat transfer fluid, or other fluid.

<FIG> illustrates an embodiment of a catheter <NUM> having a temperature control balloon <NUM>. The temperature control balloon is expanded by and filled with heat transfer fluid. Unlike catheter <NUM>, this catheter <NUM> does not include an additional lumen <NUM>.

<FIG> illustrates an embodiment of a catheter <NUM> having a temperature control balloon <NUM>, a valve <NUM>, and an additional lumen <NUM>. Like the temperature control balloon <NUM> of catheter <NUM>, the temperature control balloon <NUM> of catheter <NUM> is expanded by and filled with heat transfer fluid. When the balloon <NUM> is filled with heat transfer fluid, in addition to controlling the temperature (e.g., heating or cooling) materials adjacent to the outside of the balloon, the heat transfer fluid may change the temperature of fluid traveling through the additional lumen <NUM>. The valve <NUM> may be configured to control the flow of heat transfer fluid through the catheter <NUM>.

<FIG> illustrates an embodiment of a catheter <NUM> including a plurality of balloons <NUM>, an inlet <NUM>, and an outlet <NUM>.

Various embodiments may comprise sensors for monitoring temperature, intracranial pressure, and other measurements.

Pressure sensors. In certain embodiments, a catheter may include pressure sensors positioned on, in, or about the catheter. The pressure sensors may be used to detect conditions in the overall flow circuit, and to detect blockages. A balloon may be positioned over the catheter and may be used to deploy flexible pressure sensors. In other embodiments, the flexible pressure sensors may be printed on a substrate (e.g., silicone).

Temperature sensors. A temperature sensor (e.g., fiber optic or thermocouple) may be used to sense a temperature or temperature gradient at a given point or series of points (e.g., at a treatment site <NUM>, along a catheter, along tubing <NUM>, in the system <NUM>, or in other locations). A temperature sensor may be configured to collect a first reading in the spinal cord or in the brain parenchyma or in the tissue itself. There may be a tip sensor and a stepped algorithm such that for every interval of x seconds the temperature is checked. In another embodiment, a temperature sensor outside the body may read from a temperature sensor in the tissue as well as a temperature sensor in the CSF in the body and an algorithm may read temperature an interval of x seconds it checks the temperature. While there is a difference in temperature, the system may be configured to continue to cool or increase the flow rate of heat transfer fluid.

Surrogate volume measurements. In certain embodiments, it may be desirable to monitor the volume of fluid that has moved through the system <NUM>. For example, embodiments controlling temperature based on controlling the flow of cooled CSF back into the system may be flow-rate dependent. In such embodiments, volume of cooled CSF returning to the system may need to be tracked in order to determine whether the cooled CSF overcomes the heat that that blood is bringing back to the brain.

In some embodiments, the rate at which the fluid is withdrawn from the treatment site <NUM> is between approximately <NUM>/min and approximately <NUM>/min. In some embodiments, the fluid rate may be approximately <NUM>/min to approximately <NUM>/min or approximately <NUM>/min to approximately <NUM>/min. Fluid may be returned at approximately the same rate as fluid is withdrawn, or it may be a different rate. However, the amount withdrawn or returned may be higher or lower depending on the application. The amount may vary depending on various factors including but not to the type of fluid being withdrawn, the viscosity of the fluid, the amount of fluid in the treatment site <NUM>, and other factors. The viscosity of the fluid may vary over time, and depending on the particular subject <NUM>. For example, the viscosity of CSF may be different in a subject <NUM> with meningitis than in a subject <NUM> who does not have meningitis.

As another example, during a surgery intracranial pressure may drop it may be desirable to determine the volume of fluid that had been removed. The volume removed may be measured in various direct and indirect ways. In certain embodiments, one or more flow meters may be used. For example, a flow meter may be placed to monitor the amount of fluid withdrawn from the treatment site <NUM>. Another flow meter may be placed to monitor the amount of fluid returned to the treatment site <NUM>. In implementations where fluid is stored by the system (e.g., in a bag), the volume of fluid in the bag may be measured to determine a volume withdrawn from the treatment site <NUM>. For example, the bag may be weighed to determine the volume removed.

Cerebral blood flow measurements. In certain embodiments, the system <NUM> may also measure cerebral blood flow. For example, the Kety-Schmidt inert-gas technique, transcerebral double-indicator dilution technique, and/or other techniques may be used to measure the cerebral blood flow of the patient. The monitoring of cerebral blood flow may be used to sense and avoid vasoconstriction.

Electroencephalogram (EEG) monitoring. In certain implementations, the system <NUM> may include or cooperate with an EEG to read signals from the brain of the subject. In particular, there may be EEG electrodes or other sensors disposed on the catheter of the system. In addition to or instead of EEG electrodes on the catheter, there may be surface electrodes placed on the skin of the subject. The monitoring may be continuous or intermittent. The results of the EEG monitoring may be used to facilitate various outcomes, including but not limited to prediction and prognosis of brain activity and function following rewarming. EEG monitoring may also titrate therapy for seizure control.

Evoked potential monitoring. In certain implementations, the system <NUM> may be configured to receive evoked potential test results and/or conduct evoked potential tests. Evoked potential tests may measure electrical activity of the nervous system (e.g., portions of the spine) of the subject in response to stimulation of nerves. The evoked potential test results may be used to titrate the amount of cooling. For instance, the system may detect a <NUM>% reduction in evoked potential and increase or decrease the temperature. The system may reduce the frequency of evoked potentials by a percentage and keep reducing the temperature until a minimum threshold (e.g. a temperature threshold or an evoked potential test result threshold) is reached.

Measuring intracranial pressure. The system <NUM> may be configured to read intracranial pressure and use the readings to modify therapy. In some embodiments, the intracranial pressure may be estimated based on a reading of intraocular pressure. In some embodiments, the system <NUM> may extrapolate thermomodulation, flow signatures, temperature readings, flow rate readings, and other parameters as a surrogate intracranial pressure. For example, a particular sensed flow rate reading may be extrapolated to determine whether there his high or low intracranial pressure.

The systems and methods described herein may comprise various safety systems to promote the safe treatment of the subject <NUM>.

Vasoconstriction avoidance module. For certain individuals, excessive cooling can result in vasoconstriction, which may cause headaches or other issues. Vasoconstriction may manifest itself as a change in pressure. Embodiments of disclosed systems may track pressure and incorporate it into a system-management algorithm. In particular, the algorithm may be configured to cause cooling until a pressure drop is detected (e.g., about <NUM>-<NUM> mmHg, about <NUM> mmHg, or other drops in pressure) and then hold cooling at that level.

Compartmentalization detection. In certain uses of temperature control systems, there may be a risk of compartmentalization within a CSF-carrying space. For example, in procedures addressing hydrocephalus, subarachnoid hemorrhage, stroke, or clots in the CSF-carrying space, it may be desirable to utilize a system having multiple pressure sensors to detect potential compartmentalization, By contrast, in certain uses, there may be less of a need for compartmentalization detection. For example, thoracic abdominal aneurysm procedures, it may be known that there is going to be good communication between different compartments of a brain or other CSF-carrying spaces.

In some embodiments, the system <NUM> may be configured to monitor the fluid flow rate and pressure at multiple points within the brain, other CSF-carrying spaces, and/or the catheter itself. If there is normal pressure hydrocephalus or other blockages, then there may be spikes in pressure and decreased flow as the catheter attempts to withdraw fluid and cannot. Depending on the measured pressure and/or flow rate, a gradient of values may result. Depending on where the low or high reading is located (e.g., at or near a particular pressure or flow sensor), the location of the problem may be triangulated. For example, the system may determine that the problem is located within a cervical, thoracic, or ventricular space.

Blockage detection and prevention. Certain embodiments may be configured to avoid, detect, and address potential blockages within the system. For example, in certain embodiments, the catheter may comprise multiple inlets and outlets to minimize the effect of clogs or blockages. The lumens of the catheter may include particular shapes to discourage clogging. For example, the lumens may combine various sizes, shapes (e.g., square, oval, and circular) to discourage clogging. Blockages may be detected through the monitoring of expected and actual flow rates, pressure, and other characteristics. For example, if a measured pressure is significantly higher or lower than expected, this reading may indicate a potential clog or blockage within the system.

Safety Mechanisms. The system may be configured to determine how and/or to what extent the subject is responding to therapy delivery. In some embodiments, the system may be configured to determine whether the subject is reacting adversely to therapy delivery. For example, the system may determine whether the subject is too cold, the subject is experiencing a spinal headache, or other adverse reactions. The system may also determine whether the subject is not reacting or not reacting enough to the therapy. In response to determine that the subject is reacting adversely or insufficiently to the therapy, the system may alter treatment parameters, such as duration of therapy or ramping of temperature or flow. Gradual ramping of temperature or flow rate can provided greater safety than causing rapid changes in temperature or flow rate. In some embodiments, the system may measure the subject's response to therapy based on readings of cardiovascular, nervous system, or other parameters or readings. The parameters and readings may include, but need not be limited to heart rate, blood pressure, blood oxygen level, EEG results, evoked potential, and/or other readings or combinations thereof.

Extracorporeal temperature control. <FIG> illustrates a method <NUM> for using a treatment unit for the treatment of biologic fluids, including a starting step <NUM>, a withdrawing a volume of fluid step <NUM>, a treating the volume of fluid step <NUM>, a measuring characteristics step <NUM>, a returning the volume of fluid step <NUM>, a determining step <NUM>, an updating parameters step <NUM>, and an ending step <NUM>. The method <NUM> may be utilized with various embodiments, including system <NUM>.

While the method <NUM> is described as being performed on a particular volume of fluid, the system may operate on a continuous flow of fluid. That is, the system <NUM> need not necessarily withdraw a volume of fluid, wait for the volume to be processed and returned, and then withdraw another volume of fluid. The method may follow a continuous process. Similarly, while <FIG> appears to illustrate a series of consecutive steps, the steps of the described method may occur concurrently. For example, the system <NUM> may concurrently perform some or all of the steps illustrated in <FIG>. For instance, the system <NUM> may concurrently withdraw and return fluid.

The method <NUM> may begin at the starting step <NUM>. This step <NUM> may include activating one or more components of the system <NUM>. This step <NUM> may also include or follow various preparation steps. Such steps may include installing temperature control components, adding heat transfer fluid, installing filtration components, selecting and preparing the treatment site <NUM>, installing tubing <NUM>, calibrating components, priming components of the system, and other steps.

The selecting and preparing the treatment site <NUM> step may include choosing a particular treatment site <NUM>. For example, a healthcare professional may select a subject <NUM> that may benefit from having treatment performed at a treatment site <NUM>. Preparing the treatment site <NUM> may include identifying an anatomical location for a procedure to access the treatment site <NUM> (for example, in a spinal portion <NUM>, as shown in <FIG>), sterilizing the location, or otherwise preparing the treatment site <NUM> for the procedure. Selecting and preparing the treatment site <NUM> may be performed according to the systems and methods described within this application or through other means.

In some embodiments, preparing the treatment site may include placing an epidural needle into an introducer, accessing the subarachnoid space of the subject <NUM> using the needle and introducer, removing the needle while leaving the introducer in place, placing a guidewire, securing a catheter to the patient using a fixation device, peeling away the introducer, connecting the treatment system <NUM> to the catheter, and implanting the catheter using over-the-wire placement techniques. During the preparation, fluoroscopy may be used to verify access to the subarachnoid space, verify placement of the guidewire, and confirm placement of the catheter.

Installing tubing <NUM> may include connecting various components of the system <NUM>. This step may include installing tubing <NUM> and the catheter <NUM> to the treatment site <NUM>. This step may include inserting a multi-lumen catheter into an anatomical location to place the treatment site <NUM> in fluid connection with the system <NUM> to enable fluid to be drawn into the port <NUM> and returned to the treatment site <NUM>.

Calibrating components may include setting initial parameters for the use of the system <NUM>. This step may include establishing an initial flow rate, an initial temperature control rate, an initial pressure, and other initial parameters or system settings. The initial parameters may be based on observed or predicted clinical measures, including but not limited to an estimated amount of fluid in the treatment site <NUM>, the health of the subject, the predicted ratio of retentate to permeate, and other factors.

Priming the system <NUM> may include adding a priming solution to one or more of the components of the system <NUM>. Depending on the configuration of the system <NUM>, priming may be necessary for one or more components to function effectively. Depending on the treatment site <NUM>, fluid, and the subject, one or more components may be primed to improve comfort and health of the subject. In certain applications, the system <NUM> may be primed to enable the return of a volume of fluid while simultaneously withdrawing a volume of fluid. This may be especially useful for applications where the treatment site <NUM> has a relatively small volume of fluid (e.g., CSF) or is otherwise sensitive to relative changes in volume. Depending on the type of treatment, the length of the procedure, and other factors, priming fluid may be added during the filtration procedure to make up for fluid lost or used during the procedure.

At step <NUM>, a volume of fluid is withdrawn from the treatment site <NUM>. In certain circumstances, the fluid may be withdrawn using a pump or device located within the system <NUM> (e.g., pump <NUM>). The pump may be used to withdraw a volume of fluid from the treatment site <NUM>. Once the fluid is withdrawn from the treatment site <NUM>, the fluid may pass through the tubing <NUM> and into the filtration system <NUM> via port <NUM>.

At step <NUM>, the volume of fluid is treated. The treatment of the fluid may include temperature control (e.g. using temperature control unit <NUM>), warming (or allowing the fluid to warm), filtering (e.g., using filter <NUM>), other treatment techniques, and/or combinations thereof. In certain embodiments, the fluid may be successively or progressively treated, such as by being cooled and/or filtered again through another process, system, or unit.

In certain embodiments, the rate of temperature control or warming may be altered by changing the heat transfer fluid used (e.g., changing from a heat transfer fluid having a high specific heat capacity to a heat transfer fluid having a low specific heat capacity).

For example, if the heat transfer fluid is saline, it may be replaced with perfluorocarbon to achieve a different rate of temperature control. In particular, there may be an embodiment using saline as a heat transfer fluid and after a particular amount of time (e.g., three cycles of checking sensors) if the measured temperature has not changed by a significant amount (e.g., <NUM>), then the saline may be removed from the system and replaced with a different heat transfer fluid (e.g., a perflurocarbon) to attempt to change the temperature.

There are various means for rewarming fluid. In certain embodiments, the flow rate of heat transfer fluid may be reduced (e.g., the flowrate may be reduced from about <NUM> per minute to about <NUM> per minute to about <NUM> per minute), or the amount of heat transfer fluid used may be reduced. Other means may be used as well.

At step <NUM>, characteristics of the subject <NUM>, the treatment site <NUM>, the fluid, and/or the system may be measured. Measuring characteristics may include intermittent or continuous sampling and/or monitoring of characteristics or parameters of interest. While this step <NUM> is shown as occurring after the filtration of the fluid <NUM>, the step <NUM> may take place at any point during the process <NUM> where useful data may be gathered. In certain embodiments, measuring characteristics may include measuring the characteristics of the fluid withdrawn from the treatment site <NUM> before, during, or after treatment. The characteristics measured may include the presence or amount of particular contaminants, proteins, compounds, markers, and other fluid components present. As another example, the ratio of permeate volume to retentate volume, the fluid flow rate from the treatment site <NUM>, fluid temperature, fluid opacity or translucency or transparency, an absolute retentate flow rate, and the rate of fluid flow to the treatment site <NUM> also may be measured. The performance characteristics of the system <NUM> may also be measured. For example, the efficiency of the filter <NUM>, the status of the filter <NUM> (for example, via the interface <NUM>), and other markers of system <NUM> performance may be measured.

In certain embodiments, the characteristics measured may include information about a subject or input by a healthcare provider. For example, the system <NUM> may monitor the blood pressure, heart rate, stress, and other information of the subject. In addition to quantitative characteristics, qualitative measurements may be made as well. For instance, subject discomfort and other qualities may be measured. These and other data may be measured by the sensor <NUM> and/or be input into the system by an input device (for example, keyboard, touch screen, subject-monitoring device, and other devices for receiving input) operably coupled to the system <NUM>.

At step <NUM>, a volume of fluid is returned to the treatment site <NUM>. In certain embodiments, the fluid is returned to the treatment site <NUM> as soon as fluid filtration has been completed. In certain embodiments, the flow rate of the fluid may be controlled. For example, a volume of fluid may be buffered in an area of the system <NUM> for a time before being returned to the treatment site <NUM>. Buffering may be used to smooth the return rate of the fluid, to allow time for the fluid to reach a particular temperature, to allow time for a particular additive to mix within the fluid, and for other reasons.

In certain embodiments, the rate and/or pressure at which the fluid is returned to the treatment site <NUM> is controlled (for example, by a flow regulator). For example, the return of fluid is controlled so that the fluid is returned at such a rate or in such a manner as to maintain homeostasis within the treatment site <NUM>. In certain embodiments, this may be accomplished by returning fluid at the same rate at which fluid is currently being withdrawn from the system. In certain embodiments, the fluid may be returned at substantially the same flow rate at which it was removed. The fluid volume removed from the system and returned to the system may not be equal. This may be the case when removing a significant quantity of contaminants from a treatment site <NUM>. In certain embodiments, the difference may be made up through the addition of additional fluid.

In certain embodiments, a particular volume of additional fluid may be returned to the treatment site <NUM>. The additional fluid may be fluid that was not withdrawn from the treatment site <NUM>, previously withdrawn from the treatment site <NUM>, withdrawn from a different treatment site <NUM>, synthetically created, mixtures of these, or otherwise different from the volume removed from the treatment site <NUM> in step <NUM>. The return of additional fluid may be used to, for example, compensate for a volume of fluid that was filtered out, especially in circumstances where the treatment site <NUM> comprised only a small amount of fluid at the start <NUM>.

In certain embodiments, one or more therapeutic agents may be added to the fluid prior to its return to the treatment site <NUM>. The fluid may be treated or mixed with a particular pharmacological agent. For example, when the fluid is CSF, the agent may be configured to bypass the blood-brain barrier. The agents may include, but need not be limited to, antibiotics, nerve growth factor, anti-inflammatory agents, pain-relief agents, agents designed to be delivered using intrathecal means, agents designed to affect a particular condition (e.g., meningitis, Alzheimer's disease, depression, chronic pain, and other conditions), and other agents.

As a specific example, the treatment site <NUM> may be a CSF-containing space of a subject, such as the subarachnoid space or another space known or thought to contain CSF. The space may only have a total of approximately <NUM> of CSF, and if the level drops below a certain threshold (for example, approximately <NUM>), the subject may suffer undesirable side effects. If a particular large amount of the existing CSF comprises undesirable compounds, the volume of permeate may be small enough to cause the fluid levels in the treatment site <NUM> to drop below the threshold. Consequently, the system <NUM> may return a volume of additional fluid (for example, artificial CSF or other suitable fluid) to adjust for the difference between the amount of withdrawn CSF being returned and the amount needed to be returned in order to maintain the volume of the treatment site <NUM> above the threshold amount.

In certain embodiments, the withdrawal and return of the fluid may occur in a pulsed manner. For example, the system <NUM> may withdraw a particular volume and then cease withdrawing additional fluid. The withdrawn volume is processed by the filtration or other systems and buffered (for example, at the combiner <NUM>). Filtered amount from the buffer may be returned to the treatment site <NUM> at about the same rate and/or for the about same total volume as a next volume is withdrawn from the treatment site <NUM>. This process may allow the system to maintain treatment site <NUM> volume levels relatively consistent and may be useful in circumstances where the processing time (for example, the time between the fluid being withdrawn from and returned to the treatment site <NUM>) is long.

At step <NUM>, a determination is made. The determination may be made by, for example, a healthcare professional, a processor system, or a combination thereof. For example, the healthcare professional may analyze the measured characteristics and come to a conclusion. As another example, the processing unit <NUM> may analyze the measured characteristics using an algorithm or through other mechanisms. The determination may be based on the measured parameters, a timer, a schedule, or other mechanisms. The determination may be used in order to change the parameters of the system <NUM> over time and to address particular measured characteristics.

For example, a determination may be made regarding the rate of cooling and/or warming of the treatment site. For example, based on the measured characteristics, the rate of temperature control may be too low or too high based on a target treatment time or treatment rate.

As another example, a determination may be made regarding the flow rate at which the fluid is being withdrawn and/or returned to the treatment site <NUM>. For example, it may be desirable to maintain substantially the same withdrawal and return rate of the fluid. Specifically, if more fluid is being withdrawn from the treatment site <NUM> than is being returned, then the volume of fluid in the treatment site <NUM> may be decreasing overall. This may be undesirable because for certain fluids and certain treatment sites <NUM>, if the volume of the treatment site <NUM> passes a particular threshold, undesirable side effects may occur. For instance, where the fluid being withdrawn is CSF, the flow rate may be such that the volume of CSF removed from a human subject does not exceed about between approximately <NUM> and approximately <NUM> over the course of one hour. That is, the volume of fluid does not decrease more than approximately <NUM> to approximately <NUM> from its original starting volume in a one hour period of time. In certain embodiments, it may be desirable to maintain an absolute retentate flow rate within a certain range of acceptable retentate flow rates. In certain embodiments, the threshold may be between approximately <NUM>/min and approximately <NUM>/min. In certain embodiments, the threshold may be approximately <NUM>/min. In certain embodiments, the threshold may be between approximately <NUM>/min and approximately <NUM>/min; however, other values may be desirable in certain circumstances.

Based on the measured characteristics, it may be determined that the best way to address the disparity in the withdrawal and return rates may be to decrease the flow rate to reduce the overall volume of fluid lost from the system. This may mean that, although there is a net loss of fluid from the treatment site <NUM>, the loss is occurring at a slower rate. The rate may be sufficiently slow that, for example, that the subject's body produces sufficient fluid to make up for the loss.

As another example, the measured characteristics may be a subject's expressed discomfort. Withdrawing CSF from a CSF-containing space of a subject may cause symptoms of overdrainage, such as spinal headache. Symptoms of overdrainage may be able to be avoided or otherwise addressed by not withdrawing more than a threshold amount of CSF. However, the particular threshold may vary from subject to subject. As such, a predicted threshold may be different from an actual threshold and the subject may experience symptoms sooner than expected. In response to the subject expressing feelings of discomfort, the healthcare professional may determine that the parameters of the process may need to be changed.

In certain embodiments, at step <NUM>, the processing unit <NUM> and/or a healthcare professional may determine that the process should be completed. At this point, the flow moves to end step <NUM>. In certain other embodiments, at step <NUM>, the processing unit <NUM> and/or a healthcare professional may determine that the process should continue substantially unchanged. Upon that determination, the flow diagram may return to step <NUM>. In still other embodiments, at step <NUM>, the processing unit <NUM> and/or a healthcare professional may determine that the one or more parameters of the process should be changed. Upon that determination, the flow diagram may move to step <NUM>.

At step <NUM>, one or more parameters of the system <NUM> are changed in response to a determination made in step <NUM>. The parameters to be changed may include inflow rate, outflow rate, temperature control amount, and other parameters. Such parameters may be changed via, for example, the processing unit <NUM> sending a signal to the pump <NUM> or other component of the system in order to modify the parameters. In certain embodiments, the parameters may be manually changed through input received at the port <NUM>. This may include parameters entered by a healthcare professional. In certain embodiments, parameters may be updated based on the difference between the withdrawal volume and the returned volume (e.g., a waste rate), a target temperature control rate and an actual temperature control rate, and other goals.

In certain embodiments, the updating parameters step <NUM> may include changing the flow direction of the fluid. For example, a system may include a plurality of treatment systems, which the fluid may be directed to by the manipulation of a valve or other mechanisms for changing fluid flow direction. Step <NUM> may include changing the fluid flow from one treatment system to a different treatment system. This may be in response to determining that a second treatment system is more suited for filtering particular contaminants than a first filtration system, for example.

In certain embodiments, the updating parameters step <NUM> may include modifying the positioning of the tubing at the treatment site <NUM>. For example, one or more inflow or outflow tubes <NUM> may become clogged or otherwise be operate at a reduced capacity.

In response, the tubing <NUM> may be adjusted or otherwise modified to address the reduced capacity issue. The healthcare professional may be alerted to the issue by a light, alarm or other indicia.

In certain embodiments, the updating parameters step <NUM> may include cleaning or otherwise modifying one or more components of the system <NUM>, such as the filter <NUM>. This may be accomplished by, for example, changing back pressure and pump speed. In certain embodiments, the updating parameters step <NUM> may include sensing characteristics of the system to determine whether the filter <NUM> or other components of the system are experiencing clogging. The sensed characteristic may include reading an alert state of the filtration system or detecting an increase in filter pressure with no change to system flow rates or other parameters of the system. Responsive to determining that there may be a clog in the system <NUM>, the flow rate through the retentate port of the filters may be increased. The increased flow rate may be the result of a user or the system opening a back pressure valve (e.g., a backpressure valve of a flow regulator). The opening of the valve may result in a surge of fluid through one or more retentate ports of one or more filters into a waste collection area. The surge of fluid may result in the flow returning to the treatment site <NUM> reducing to zero or even a negative rate. Thus, the operator or system controlling the flow rate may take into account the volume of fluid lost and the possible effects on the patient as a result of this filter clearance mechanism.

At step <NUM>, the process comes to an end. After the process is completed, various wind-up steps may be performed, including but not limited to, applying a bandage to the subject, disassembling one or more components of the system <NUM>, analyzing an amount of the withdrawn fluid, analyzing the retentate, and other steps.

Temperature control in the treatment site. <FIG> illustrates a method <NUM> for temperature control at a treatment site <NUM>. In particular, the method <NUM> may be a modified version of the method <NUM> of <FIG> directed toward direct temperature control at the treatment site <NUM>. The method <NUM> may comprise a starting step <NUM>, an applying treatment step <NUM>, a measuring characteristics step <NUM>, a determining step <NUM>, an updating parameters step <NUM>, and an ending step <NUM>. The method may be utilized with certain embodiments, including system <NUM>.

The starting step <NUM> may be substantially similar to step <NUM> of the method <NUM> and focused on temperature control directly within the treatment site <NUM>. In particular, this step <NUM> may include inserting a catheter <NUM> into a treatment site, the catheter <NUM> having at least one temperature control lumen configured for the circulation of heat transfer fluid. This step <NUM> may also include preparing the treatment unit <NUM> for the temperature control and circulation of the heat transfer fluid within the catheter <NUM>. The applying treatment step <NUM> may include causing the temperature control, causing the warming, or otherwise treating the treatment site <NUM>. This may include, but need not be limited to, circulating a heat transfer fluid within a temperature control lumen of the catheter <NUM>. The heat transfer fluid may be cooled and/or warmed by the temperature control unit <NUM>. The heat transfer fluid may circulate at a particular rate, temperature, volume, and other characteristics. These characteristics may be modifiable at the temperature control unit <NUM>.

The measuring characteristics step <NUM> may include measuring characteristics of the heat transfer fluid, treatment site, and/or other portions of the system. This step <NUM> may be similar to the step <NUM> of the method <NUM>.

The determining step <NUM> may include determining how to proceed with treatment of the treatment site <NUM>. This step may be similar to the determinations made in step <NUM> of method <NUM>. For example, the determining step <NUM> may include determining how the measured characteristics compare with desired goals and targets for treatment.

According to the invention, the current rate of temperature control is compared with a desired or target rate of temperature control. The determination may be made that particular parameters of the treatment may need to be changed in order to reach a desired clinical or other outcome. If a determination is made that one or more parameters of the system <NUM> needs to or should be changed, the flow of the diagram may move to the update parameters step <NUM>. If a determination is made that treatment should end, then the flow may move to the ending step <NUM>.

The update parameters step <NUM> may include modifying one or more parameters of the system <NUM> based on the determining step <NUM>. The update parameters step <NUM> may be similar to the update parameters step <NUM>. This step <NUM> may include changing the temperature of the heat transfer fluid, the flow rate of the heat transfer fluid, the type of heat transfer fluid, and/or other parameters of the treatment to more closely track a desired treatment target.

At step <NUM>, the process comes to an end. After the process is completed, various wind-up steps may be performed, including but not limited to, applying a bandage to the subject, disassembling one or more components of the system <NUM>, analyzing the results of treatment, and/or other steps.

<FIG> illustrate example methods for controlling treatment and updating parameters. In particular, <FIG> illustrates an example method <NUM> for controlling temperature. The method for controlling temperature may be used in conjunction with or instead of the methods described in <FIG> and <FIG>. The method may include a starting treatment step <NUM>, a reading sensors step <NUM>, a determining if a target is reached step <NUM>, a performing a health check step <NUM>, a continuing treatment step <NUM>, a determining whether to end treatment step <NUM>, and a stopping treatment step <NUM>.

The method <NUM> begins at the start treatment step <NUM>. The method <NUM> may start after various preparatory steps have been performed. In particular, a temperature control and sensing system may be configured to cool a fluid and read sensors. For example, a temperature control catheter may be inserted into a CSF-containing space of a subject's spine, and/or into one or more cerebral ventricles of the subject. The system may be configured to cool the fluid within the subject (e.g., by circulating heat transfer fluid through the catheter) and/or withdraw the fluid, cool the withdrawn fluid, and return the fluid.

The reading sensors step <NUM> may comprise reading sensor information from various sensors. The sensors may be temperature sensors, EEG sensors, intracranial pressure sensors, flow rate sensors, and/or other sensors for reading information pertaining to the subject, the fluid, or other sources. In certain embodiments, reading sensors may comprise measuring a functional biomarker (e.g., intracranial pressure, tissue temperature, and cytokine markers). In some embodiments, one or more sensors (e.g., pressure within the catheter or temperature) can be located on or within a catheter, such as at the tip of the catheter. Sensor information may be used in order to make decisions as to whether to increase, decrease, alter, or maintain a treatment.

The determining if a target is reached step <NUM> may include using the information received from step <NUM> to determine whether a target is reached. For example, the target may be a target temperature, a target flow rate, a target pressure, a target time, other targets, or a combination thereof. A target may be reached if the measured value meets, exceeds, passes, or falls within a particular range of a target value. If the target is reached, then the flow may move to the determining whether to end treatment step <NUM>. If the target is not reached, then the flow may move to the performing a health check step <NUM>. In addition, following this step <NUM>, the target may be modified. A treatment of a subject may include one or more targets. If there are a plurality of targets, then there may be dependencies between targets (e.g., a first or a second target must be reached before moving to a third target).

In some embodiments, determining whether a target is reached may be as simple as determining whether the system is set to a target mode or has changed a target mode. For example, if the system was in a cooling mode and then the system detects a change to a maintain mode, then the method may move to the determining whether to end treatment step <NUM>.

The performing a health check step <NUM> may include checking the health of the subject. The check may be performed using information read from the sensors in step <NUM>, additional information gathered for this step <NUM>, input from a health professional (e.g., observations made by a doctor), input from the subject (e.g., expressed discomfort), other sources, or combinations thereof. The check may result in a favorable or unfavorable health determination. For instance, an unfavorable health check may be the result of expressed discomfort by the patient, a core body temperature that is dangerously low, abnormal heart rate, abnormal heart rhythm, abnormal EEG results, abnormal intracranial pressure, sensor readings outside of expected ranges, other indications of an unfavorable health state in the patient, or combinations thereof. A favorable health check may be the result of a lack of unfavorable health determinations, sensed values in expected ranges, other indications of a favorable subject health state, or a combination thereof. If the health check is unfavorable, then the flow may move to the determining whether to end treatment step <NUM>. If the health check is favorable, then the flow may move to the modifying treatment step <NUM>.

The health check may also include a check of the health of the system delivering treatment. For example, a detection of a clog in the system may result in an unfavorable health check. As another example, if a modification of treatment has not resulted in a desired, predicted, or expected change in sensor readings, there may be a problem with the system that may result in an unfavorable health check.

The continuing treatment step <NUM> may involve continuing treatment at current levels or modifying treatment. The modification of treatment may be based on the difference between the sensor readings and the target (as may be performed as part of step <NUM>), the health check of step <NUM>, the determination as to whether to end treatment <NUM>, or other factors. Various parameters of treatment may be modified, including but not limited to those already described in the updating parameter step <NUM> described above. Following the modifying treatment step <NUM>, the flow may move to step <NUM>.

The determining whether to end treatment step may <NUM> be reached following either an unfavorable health check in step <NUM> or the reaching of a target in step <NUM>. If the target is reached and there are no more targets to achieve, then this step <NUM> may result in a decision end treatment. If this step <NUM> is reached as a result of an unfavorable health check, then treatment may need to be ended, for example, depending on the severity of the unfavorability of the health check. For example, if the results of the health check indicate a slight trend toward a negative health state (e.g., an increase in intracranial pressure that may be the precursor of a headache), then the decision may be made to continue treatment but without increasing a treatment rate (e.g., the rate of cooling or the rate of rewarming), at a decreased treatment rate, at a maintained treatment rate.

The stopping treatment step <NUM> may be reached from the decision in step <NUM> to end treatment. Once treatment is stopped, various post-treatment wrap-up steps may be performed, including but not limited to those described above in reference to step <NUM>. <FIG> illustrates an example target cooling pattern for CSF. In particular, at time t<NUM>, the temperature is initial temperature Ti. The CSF is then cooled. As illustrated, the CSF is cooled until it reaches the target temperature Tt at a target time t<NUM>. The CSF is then maintained at the target temperature Tt until time t<NUM>. Then the target temperature Tt is maintained until time t<NUM>. From time t<NUM> to the time t<NUM> the fluid is warmed to or allowed to warm to a final temperature Tf. The cooling and re-warming gradients may be managed by the method described in <FIG>. Other cooling patterns are contemplated as being within the scope of the invention, with different slopes, transitions, lengths of time, temperature adjustments, etc..

For example, the target temperature Tt may include, but need not be limited to, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM> to about <NUM>, about <NUM>, about <NUM>, about <NUM>, or other temperatures. The time from an initial time t<NUM> to a target time t<NUM> may include, but need not be limited to, about <NUM> minutes to about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> seconds to about <NUM> seconds, about <NUM> seconds to <NUM> seconds, or other periods of time. The target temperature Tt may be maintained until time t<NUM>, which may include, but need not be limited to, about <NUM> minutes to about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> seconds to about <NUM> seconds, or about <NUM> seconds to about <NUM> seconds from the time that target time t<NUM> was reached. The fluid may then be warmed to or allowed to warm to a final temperature Tf, which may include, but need not be limited to, the initial temperature Ti, average human body temperature (approximately <NUM>), or other temperatures. The time from time t<NUM> to time t<NUM> may include, but need not be limited to, about <NUM> minutes to about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> minutes, about <NUM> seconds to about <NUM> seconds, about <NUM> seconds to about <NUM> seconds, or for other periods of time.

In some embodiments, the treatment period may be approximately <NUM> hours. For example, in embodiments directed toward subjects with traumatic brain injury, the total treatment time may be approximately <NUM> hours. This treatment length may result in a reduction in cytokine levels by more than <NUM>% from a baseline in a system having flow rates of approximately <NUM> milliliters per hour.

Target Cooling Pattern. In an embodiment applying the target cooling pattern of <FIG> to the method of <FIG>, time t<NUM> is <NUM> minutes, initial temperature Ti is about <NUM>, target temperature Tt is about <NUM>, target time t<NUM> is about <NUM> minutes, time t<NUM> is about <NUM> minutes (t<NUM> - t<NUM> = about <NUM> minutes), final temperature Tf. is about <NUM>, and t<NUM> is about <NUM> minutes (t<NUM> - t<NUM> = about <NUM> minutes). In some embodiments, the system <NUM> may have predefined modes to initiate mild, moderate, or deep hypothermia; maintain temperature; monitor changes in pressure, flow, and temperature to ensure that the system is functioning properly; and manage the cooling and draining status of the subject <NUM>. In some embodiments, the target temperature may vary based on location of measurements. For example, during hypothermia the core brain temperature may be maintained between about <NUM> to about <NUM>, in accordance with the cold saline infusing speed. After cooling begins, the deep brain temperature will decrease to about <NUM> and the subcortical brain temperature may reach approximately <NUM>. This temperature gradient between the brain surface and the deep brain may vary based on blood supply. In some embodiments, multiple temperature sensors may be used (e.g., located on the catheter) and an average brain temperature may be used based on the individual temperature probes. In some embodiments, if a clinician is trying to induce deep hypothermia (e.g., about <NUM> to about <NUM>) in the subject, then the system may measure parenchyma temperature and either continue cooling or maintain temperature based on the measured temperature. If the clinician is trying to revive the patient, then a re-warming algorithm may be engaged.

Walking through the method <NUM> of <FIG>, the starting step <NUM> may begin at time t<NUM>. At step <NUM>, the system reads sensors and determines, inter alia, that the initial temperature is about <NUM>. At step <NUM>, the determination is that this is not the target temperature Tt of about <NUM>. The flow moves to step <NUM> where a favorable health check based on intracranial pressure and EEG sensor data moves the flow to step <NUM>. In step <NUM>, the flow rate of heat transfer fluid through a catheter inserted into the spinal CSF space of the subject is increased. The loop of steps <NUM>, <NUM>, <NUM> and <NUM> continues until a target rate is reached (e.g., the cooling rate is such that the target temperature Tt will be reached at approximately target time t<NUM>). The loop then continues until the current time t is the target time t<NUM>, which results in the determination that the target time and temperature has been reached at step <NUM>, so the flow moves to the determination as to whether to end treatment at step <NUM>. While this target was reached, all targets have not been reached, so the treatment continues and the flow moves to step <NUM>. At step <NUM>, the cooling rate is changed so the temperature T remains relatively constant through time t<NUM>. The loop of steps <NUM>, <NUM>, <NUM> and <NUM> then continues until the current time t is time t<NUM>. With this target reached, treatment is still not over, so the flow moves from step <NUM> to step <NUM> to step <NUM>, where the treatment is modified so the temperature T increases at a rate such that it will reach final temperature Tf at time t<NUM>. Once these targets are met, treatment ends.

CSF Cooling Cycle (Spinal Portion). <FIG> illustrate systems and methods for withdrawing, cooling, and returning CSF in a spinal region according to some embodiments. In particular, <FIG> illustrates CSF being withdrawn from a target lumbar cistern <NUM> using a first plurality of ports <NUM> of a catheter <NUM>, the withdrawn CSF being processed in a treatment unit <NUM> to cool or otherwise treat the CSF, and the treated CSF being returned to a target cervicothoracic junction <NUM> using a second plurality of ports <NUM> of the catheter <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM> and an outlet lumen <NUM>. CSF that is being withdrawn through the first ports <NUM> may pass through the inlet lumen <NUM> and CSF being returned through the second plurality of ports <NUM> may pass through the outlet lumen <NUM>.

The treatment cycle may begin with the withdrawal of CSF from near a treatment site <NUM> using a first plurality of ports <NUM> of an elongate catheter <NUM>. The catheter <NUM> may be deployed such that the first plurality of ports <NUM> is located within the target lumbar cistern <NUM> and second plurality of ports <NUM> is located within the target cervicothoracic junction <NUM>. The target lumbar cistern <NUM> may be located in a region near the L2, L3, and L4 lumbar vertebrae; however, other target locations may also be used. The target cervicothoracic junction <NUM> may be located in a region near the C7, T1, T2, T3, and T4 vertebrae, though other locations may be used. Next, the CSF passes through the inlet lumen <NUM> of the catheter <NUM> and enters the treatment unit <NUM> through a port <NUM>. Next, a sensor <NUM> may read the pressure of the CSF as the CSF passes through a pump <NUM>. The pressure of the CSF is taken again using a sensor <NUM> as the fluid moves towards a temperature control unit <NUM>. The temperature control unit <NUM> may modify the temperature of the withdrawn CSF. For example, the temperature control unit <NUM> may cool or warm the CSF. After the CSF leaves the temperature control unit <NUM>, the CSF passes through a sensor <NUM> configured to read the pressure of the CSF and a sensor <NUM> configured to read the flow rate of the CSF. Next, the CSF passes through the port <NUM>, the outlet lumen <NUM> of the catheter <NUM>, and leaves the catheter <NUM> through the second plurality of ports <NUM> in the target cervicothoracic junction <NUM>. The withdrawal and return of CSF may cause focal cooling of the spinal cord, a target treatment site <NUM>. The control and management of this CSF cooling cycle may be controlled and monitored by a processing unit <NUM> and/or an interface <NUM>. These components <NUM>, <NUM> may be connected to the other components of the treatment unit <NUM>.

CSF Cooling Cycle (Cerebral Ventricle). <FIG> illustrate systems and methods for withdrawing, cooling, and returning CSF in a cerebral ventricle, a treatment site <NUM>. In particular, <FIG> illustrates CSF being withdrawn from a target cerebral ventricle using a first plurality of ports <NUM> of a catheter <NUM>, CSF being processed in a treatment unit <NUM> to cool or otherwise treat the CSF, and treated CSF being returned to the cerebral ventricle using a second plurality of ports <NUM> of the catheter <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM> and an outlet lumen <NUM>. CSF may pass through the inlet lumen <NUM> after the CSF has been withdrawn through the first ports <NUM>. CSF being returned through the second plurality of ports <NUM> may pass through the outlet lumen <NUM>. The treatment process may be substantially similar to the process described with regard to <FIG>.

Cooling and CSF Filtration Cycle (Spinal Portion). <FIG> illustrate methods and systems for withdrawing, filtering, and returning CSF in a spinal portion and cooling the spinal portion. In particular, <FIG> illustrates CSF being withdrawn from a target lumbar cistern <NUM> using a first plurality of ports <NUM> of a catheter <NUM>, CSF being filtered by a filter <NUM> in a treatment unit <NUM>, and filtered CSF being returned to a target cervicothoracic junction <NUM> using a second plurality of ports <NUM> of the catheter <NUM>. The embodiment further provides cooling of a treatment site <NUM> using a temperature control unit <NUM> for cooling a heat transfer fluid that flows within the catheter <NUM> to change the temperature of the treatment site <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM>, a cooling lumen <NUM>, and an outlet lumen <NUM>. CSF may pass through the inlet lumen <NUM> after the CSF has been withdrawn through the first ports <NUM>. CSF being returned through the second plurality of ports <NUM> may pass through the outlet lumen <NUM>. Heat transfer fluid may pass through the cooling lumen <NUM>.

The cycle may begin with the withdrawal of CSF from near a treatment site <NUM> using a first plurality of ports <NUM> of an elongate catheter <NUM>. The catheter <NUM> may be deployed such that the first plurality of ports <NUM> is located within the target lumbar cistern <NUM> and second plurality of ports is located within the target cervicothoracic junction <NUM>. Other suitable locations may be used. The CSF passes through the inlet lumen <NUM> of the catheter <NUM> and enters the treatment unit <NUM> through a port <NUM>. Next, the CSF may pass through a sensor <NUM> configured to read the pressure of the CSF and then a pump <NUM>. The pressure of the CSF is taken again using a sensor <NUM> as the fluid heads towards a filter <NUM>. The filter <NUM> may separate one or more components from the CSF with the materials that were filtered out being deposited in a vessel <NUM> and the filtered CSF being returned to the spinal portion <NUM>. In particular, after the CSF leaves the filter <NUM>, the CSF passes through the port, the outlet lumen <NUM> of the catheter <NUM>, leaves the catheter <NUM> through the second plurality of ports <NUM> in the target cervicothoracic junction <NUM>.

The vessel <NUM> may be a container for storing fluid. For example, fluid leaving the filter <NUM> may be deposited in the vessel <NUM>. The fluid deposited in the vessel <NUM> may be held for storage, waste disposal, processing, testing, or other uses. The vessel <NUM> may also be a reservoir for subsequent filtering, cooling, or other processing for example, through the same or different set of filters. This fluid may or not be combined with previously filtered fluid.

Before, during, or after the filtration of the CSF, a temperature control unit <NUM> may cool or warm a volume of a heat transfer fluid. The heat transfer fluid may then flow within the cooling lumen <NUM> of the catheter <NUM> to cause cooling at the treatment site <NUM>. Cooling and CSF Filtration Cycle (Cerebral Ventricle). <FIG> illustrate embodiments of systems and methods for withdrawing, filtering, and returning CSF in a cerebral ventricle. In particular, <FIG> illustrates an embodiment of CSF being withdrawn from a cerebral ventricle using a first plurality of ports <NUM> of a catheter <NUM> and filtered by a filter <NUM> in a treatment unit <NUM>, with the filtered CSF being returned to the cerebral ventricle using a second plurality of ports <NUM> of the catheter <NUM>. The embodiment further provides cooling of a treatment site <NUM> using a temperature control unit <NUM> for cooling a heat transfer fluid that flows within the catheter <NUM> to change the temperature of the treatment site <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM>, a cooling lumen <NUM>, and an outlet lumen <NUM>. CSF that is being withdrawn through the first ports <NUM> may pass through the inlet lumen <NUM> and CSF being returned through the second plurality of ports <NUM> may pass through the outlet lumen <NUM>. Heat transfer fluid may pass through the cooling lumen <NUM>. The treatment process may be substantially similar to the process described with regard to <FIG>.

Cooling and Draining CSF Cycle (Spinal Portion). <FIG> illustrate embodiments of systems and methods for draining CSF from a spinal portion and cooling the spinal portion. In particular, <FIG> illustrates CSF being withdrawn from a target lumbar cistern <NUM> and/or a target cervicothoracic junction using a first and/or second plurality of ports <NUM>, <NUM> of a catheter <NUM> and the withdrawn CSF being deposited in a vessel <NUM>. As with all embodiments, any suitable location may be used. The embodiment further provides cooling of a treatment site <NUM> using a temperature control unit <NUM> to cooling a heat transfer fluid that flows within the catheter <NUM> to change the temperature of the treatment site <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM> and three cooling lumens <NUM>. Withdrawn CSF may pass through the inlet lumen <NUM>. Heat transfer fluid may pass through the cooling lumen <NUM>.

The cycle may begin with the withdrawal of CSF from at or near a treatment site <NUM> using a first and/or second plurality of ports <NUM>, <NUM> of an elongate catheter <NUM>. The catheter <NUM> may be deployed such that the first plurality of ports <NUM> is located within the target lumbar cistern <NUM> and second plurality of ports is located within the target cervicothoracic junction <NUM>. The CSF passes through the inlet lumen <NUM> of the catheter <NUM> and enters the treatment unit <NUM> through a port <NUM>. Next, the CSF may pass through a sensor <NUM> configured to read the pressure of the CSF and then a pump <NUM>. The CSF is then deposited in a vessel <NUM>.

Before, during, or after the filtration of the CSF, a temperature control unit <NUM> may cool or warm a volume of a heat transfer fluid. The heat transfer fluid may then flow within the cooling lumen <NUM> of the catheter <NUM> to cause cooling at the treatment site <NUM>. The heat transfer fluid may pass through a sensor <NUM> configured to read the fluid's pressure and a sensor <NUM> to read the fluid's flow rate.

Cooling and Draining CSF Cycle (Cerebral Ventricles). <FIG> illustrate embodiments of systems and methods for draining CSF from a cerebral ventricle and cooling the cerebral ventricle. In particular, <FIG> illustrates CSF being withdrawn from a cerebral ventricle using a first and/or second plurality of ports <NUM>, <NUM> of a catheter <NUM> and the withdrawn CSF being deposited in a vessel <NUM>. The embodiment further provides cooling of a treatment site <NUM> using a temperature control unit <NUM> for cooling a heat transfer fluid that flows within the catheter <NUM> to change the temperature of the treatment site <NUM>. <FIG> illustrates portions of the catheter <NUM>, including regions where the first and second plurality of ports <NUM>, <NUM> may be disposed. <FIG> illustrates a cross section of the catheter <NUM>, including an inlet lumen <NUM> and three cooling lumens <NUM>. Withdrawn CSF may pass through the inlet lumen <NUM>. Heat transfer fluid may pass through the cooling lumen <NUM>. Before, during, or after the filtration of the CSF, a temperature control unit <NUM> may cool or warm a volume of the heat transfer fluid to cause cooling at the treatment site <NUM>. The treatment process may be substantially similar to the process described with regard to <FIG>. User Interface. <FIG> illustrates an example user interface that may be used in conjunction with one or more disclosed embodiments. The user interface may include, among other things, a patient identifier, a measurement of the amount of CSF that has been processed, a length of time that a pump has been running, a listing of error codes (including a time, number, and description of the code), a graph and/or gauge of a pressure sensed at a filter, a graph and/or gauge of an amount of CSF that has been withdrawn from the subject, a graph and/or gauge of a measured flow rate, a graph and/or gauge of the amount of fluid that has flown to a waste vessel, a graph and/or gauge of the rate at which material is being deposited within the vessel, a stream of raw data from sensors, and other information as desired. The user interface may also contain various controls, such as controls for turning on or off a pump, changing how quickly fluid flows through the system (e.g., by changing a parameter of the pump), increasing or decreasing position and/or step parameters of a back pressure device, locking or unlocking the system, turning on or off automatic waste control, setting a tare, leaving a comment, and/or performing other operations.

<FIG> illustrates measured brain parenchyma temperature during a CSF cooling study in a bovine subject. Temperature of the brain parenchyma was measured at a distance of <NUM> from a cerebral ventricle, <NUM> from the ventricle, and <NUM> from the ventricle over a period of time. In the study, CSF of the bovine subject was withdrawn using a dual-lumen catheter, chilled with a chiller, and returned to the subject using the catheter. The study included the use of <NUM>-on-<NUM> temperature sensors.

As illustrated, at approximately <NUM> minutes, the flow rate of the CSF was <NUM>/min, which caused a measurable drop in the temperature of the parenchyma. At approximately <NUM> minutes, the flow rate was stopped and the temperature of parenchyma increased to approximately <NUM> at <NUM>, <NUM>, and <NUM> from the ventricle. At approximately <NUM> minutes, the flow rate was set to <NUM>/min, which caused a measurable drop in the temperature of the parenchyma. The flow rate of <NUM>/min caused the temperature to drop approximately twice as fast as the flow rate of <NUM>/min. At approximately <NUM> minutes, the flow rate was stopped and the temperature rose.

The study shows a statistically significant decrease in brain temperature even <NUM> from the ventricle using a CSF cooling technique. In this manner, CSF cooling techniques can be used to cool brain parenchyma and can present advantages compared to surface cooling.

<FIG> illustrates measured inlet and outlet pressure within a catheter over time and over a variety of CSF flow rates for a first catheter design. As illustrated, the catheter outlet pressure increases as the flow rate of the catheter increases from <NUM>/min to <NUM>/min.

<FIG> illustrates measured inlet and outlet pressure within a catheter over time and over a variety of CSF flow rates for a second catheter design. As illustrated, the catheter outlet pressure increases as the flow rate of the catheter increases from <NUM>/min to <NUM>/min.

It can be advantageous to keep catheter pressure below <NUM> mmHg for safe operation of the catheter.

Within this disclosure, connection references (for example, attached, coupled, connected, and joined) may include intermediate members between a collection of components and relative movement between components. Such references do not necessarily infer that two components are directly connected and in fixed relation to each other. The exemplary drawings are for purposes of illustration only and the dimensions, positions, order and relative sizes reflected in the drawings attached hereto may vary.

Claim 1:
A system (<NUM>) for providing focal cooling at a treatment site (<NUM>), the system comprising:
a catheter (<NUM>) designed to access the treatment site (<NUM>);
wherein the treatment site (<NUM>) includes a cerebrospinal fluid-containing space;
a treatment unit (<NUM>) coupled to the catheter (<NUM>), the treatment unit (<NUM>) including a port (<NUM>) configured to be in fluid communication with the treatment site (<NUM>);
wherein the treatment unit (<NUM>) is configured to treat fluid received through the port (<NUM>) from the cerebrospinal fluid-containing space;
wherein the treatment unit (<NUM>) is configured to compare a rate of temperature control with a target rate of temperature control and update a treatment parameter if the rate of temperature control differs from the target rate of temperature control; and
wherein the treatment unit (<NUM>) includes a temperature control unit (<NUM>) designed to cool the volume of cerebrospinal fluid received from the cerebrospinal fluid-containing space.