DESCRIPTION

METHODS OF REDUCING CEREBRAL INJURY CAUSED BY EMBOLIC

MATERIAL

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial Number 61/949,411, filed March 7, 2014, which is hereby incorporated by reference in its entirety.

BACKGROUND

1. Field of the Invention

[0002] The present invention relates generally to methods for reducing brain injury, and more particularly, but not by way of limitation, to methods for cooling the brain of a subject to reduce cerebral brain flow to reduce cerebral ischemia caused by embolic material.

2. Description of Related Art

[0003] Embolic material (debris, which can consist of gaseous, clot, liquid, and solid material) can be released into the arterial blood stream during certain medical procedures. For example, all of the following procedures often release debris into the blood stream: TAVI (transcatheter aortic valve implantation), CABG (coronary artery bypass graft), AVR (aortic valve replacement), lung transplant, atrial ablation, surgery or stenting of the common carotid artery, surgery of the aortic arch and branching vessels, cerebral angiography, cardiac angiography, coronary artery angioplasty and stent placement. Other medical procedures often release debris into the venous circulation and this debris can enter the arterial blood stream through connections between the right and left chambers of the heart. For example, orthopedic surgery has been demonstrated to result in the delivery of debris to the brain.

[0004] Once embolic material is released into the blood stream, it can lodge in distal arteries and obstruct blood flow. The final location of the embolic material is in tissue beds, and the embolic material can partly or completely obstruct blood flow in arteries causing ischemia. This obstruction may be temporary or permanent. Permanent obstruction of an artery may result in temporary interruption of blood flow to the tissue downstream since perfusion can be reestablished by flow through collateral vessels. The tissue beds to which emboli are delivered can be generally divided into cerebral and systemic (non-cerebral) tissue beds.

[0005] Localized systemic (non-cerebral) ischemia is usually well tolerated and is generally of lesser clinical significance than cerebral ischemia. Localized cerebral ischemia, however, is associated with a wide range of unwanted clinical sequelae - ischemic stroke, TIA (transient ischemic attack), POCD (post-operative cognitive dysfunction) and ischemic lesions of unknown significance (which may be visible by MRI).

[0006] Ischemia is not the only cause of brain injury from embolic material. Emboli can also cause inflammation of the arteries which also causes additional brain injury. There are many complex mechanisms involved in inflammation, including irritation of the inner lining of the arteries by emboli. Furthermore, reperfusion (i.e., restoration of blood flow after an interruption) can also cause damage.

[0007] There have been previous attempts to prevent emboli from entering cerebral circulation. These methods generally work by reducing CBF (cerebral blood flow) by external compression or by filtering CBF with physical filters or screen-deflectors which are available commercially in certain geographic regions (e.g., the European Union). However, filters have not proven to be effective and, in fact, may dislodge emboli themselves as well as risk decreased blood flow to large areas of the brain.

[0008] Attempts to decrease the number of emboli reaching the brain during TAVI have not been proven to be successful. In fact, one recent study involving a recently commercialized "umbrella" type deflector device showed an increase in the number of patients with new cerebral ischemic lesions seen on MRI (when used with TAVI), and all patients who received the device in the latest study had new infarcts seen on MRI. Infarcts may have come from placing the device in the aortic arch (displacing atheromatous plaque) and from TAVI valve placement (the device did not filter or deflect a significant number of emboli). Other commercially available blood filtering devices have also shown limited ability to reduce emboli.

[0009] Some investigators have proposed physiological solutions to cerebral emboli by reducing via whole body cooling the proportion of the blood flowing to the brain. However, specific mechanisms have not been developed or described. In addition, there have been studies with direct measurement of cerebral blood flow and body blood flow that demonstrate that whole body cooling actually increases the proportion of blood flowing to the brain. In fact, in low blood flow situations, the proportion of blood flowing to the brain has been observed to double in patients that have been systemically cooled. Thus, the efficacy of whole body cooling to reduce cerebral emboli is doubtful.

SUMMARY

[0010] Accordingly, there is a need for methods for reducing the delivery of embolic material to a brain which has been dislodged by medical procedures.

[0011] In accordance with an aspect of the present disclosure, a method of reducing embolic burden on the brain resulting from embolic particles in the arterial blood stream comprises reducing the ratio of cerebral blood flow (CBF) to body blood flow (BBF) from a baseline value and performing a medical procedure (e.g., a cardiac procedure) which generates embolic material while the ratio of CBF to BBF is lowered. The ratio of CBF to BBF may be less than about 75%, 50% or 25% of the baseline ratio of CBF to BBF. The ratio of CBF to BBF may be less than about 1 : 10 to less than about 1 :20.

[0012] In accordance with another aspect of the present disclosure, a method of reducing embolic burden on the brain resulting from embolic particles in the arterial blood stream, comprises reducing the ratio of cerebral blood flow (CBF) to body blood flow (BBF) from a baseline value by reducing brain temperature relative to the body temperature to create a temperature differential.

[0013] The temperature differential may be transient, and occur between about 2 and about 20 minutes, or between about 2 and about 60 minutes. The brain-body temperature differential may be modulated to target periods of high embolic burden. The transient cooling profile may be user defined.

[0014] The temperature differential may be static for a user specified duration. The user specified duration may be greater than about 30, about 60 minutes or about two hours.

[0015] The temperature of the brain may be lowered by more than about 0.25°C.

[0016] The ratio of CBF to BBF may be reduced by selectively targeting cooling of the brain through a non-invasive method. The targeted cooling may comprise supplying a cooled fluid to the aerodigestive tract. The method may further comprise increasing body blood flow (BBF) to further reduce the ratio of CBF to BBF. The body blood flow (BBF) may be increased by warming the skin.

[0017] The ratio of CBF to BBF may be further reduced by altering pC02. Altering pC02 to reduce the ratio of CBF to BBF may cause a greater temperature differential, thereby allowing further reductions in pC02 or prolonged duration of reduced pC02.

[0018] Cerebral blood may be measured with a jugular blood catheter and CBF may be adjusted based on the measurements. The measurements may include at least oxygen saturation.

[0019] The targeted cooling of the brain may be ended by making stepwise adjustments to the temperature of cooling fluid and/or the flow rate of the cooling fluid. The adjustments may be made according to a pre-determined schedule, and the adjustments may be made according to jugular bulb catheter readings.

[0020] The targeted cooling of the brain may be made by making continuous adjustments to the temperature of cooling fluid and/or the flow rate of the cooling fluid. The adjustments may occur at a predetermined frequency, and the adjustments may be made according to jugular bulb catheter readings.

[0021] In accordance with yet another aspect, a method of protecting the brain during an induced cardiac stand-still procedure comprises inducing cardiac stand-still, cooling a long column of blood, and reperfusing the brain with the cooled long column of blood. Cardiac stand still may comprise substantially 0%, 10% or 20% of baseline blood flow. The method may further include altering pC02.

[0022] In another embodiment, the methods further comprise introducing cooling fluid to the aerodigestive tract of a subject to selectively cool the brain of the subject; reducing the ratio of cerebral blood flow (CBF) to body blood flow (BBF) from a baseline value; and performing a medical procedure that generates embolic material. In some embodiments, prior to reducing the ratio of CBF to BBF from a baseline value, the methods comprise permitting a brain temperature to body temperature gradient to occur in which the brain temperature is cooler than the body temperature. In some embodiments, prior to performing a medical procedure that generates embolic material, the methods comprise permitting the brain temperature to body temperature gradient to increase. In some embodiments, reducing the ratio of CBF to BBF comprises decreasing the level of pC0 ₂ in the blood of the subject. In some embodiments, the brain temperature to body temperature gradient is approximately 1 degree Celsius. In some embodiments, the brain temperature to body temperature gradient is approximately 3 degrees Celsius.

[0023] Any embodiment of any of the present methods can consist of or consist essentially of - rather than comprise/include/contain/have - any of the described elements and/or features. Thus, in any of the claims, the term "consisting of or "consisting essentially of can be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.

[0024] The terms "a" and "an" are defined as one or more unless this disclosure explicitly requires otherwise.

[0025] The term "substantially" is defined as largely but not necessarily wholly what is specified (and includes what is specified; e.g., substantially 90 degrees includes 90 degrees and substantially parallel includes parallel), as understood by a person of ordinary skill in the art. In any disclosed embodiment, the terms "substantially," "approximately," and "about" may be substituted with "within [a percentage] of what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.

[0026] The terms "comprise" (and any form of comprise, such as "comprises" and "comprising"), "have" (and any form of have, such as "has" and "having"), "include" (and any form of include, such as "includes" and "including") and "contain" (and any form of contain, such as "contains" and "containing") are open-ended linking verbs. As a result, a cooling device, or a component of a cooling device, that "comprises," "has," "includes" or "contains" one or more elements or features possesses those one or more elements or features, but is not limited to possessing only those elements or features. Likewise, a cooling method that "comprises," "has," "includes" or "contains" one or more steps possesses those one or more steps, but is not limited to possessing only those one or more steps. Additionally, terms such as "first" and "second" are used only to differentiate structures or features, and not to limit the different structures or features to a particular order. [0027] The feature or features of one embodiment may be applied to other embodiments, even though not described or illustrated, unless expressly prohibited by this disclosure or the nature of the embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Other characteristics and advantages of the present invention will emerge upon reading the following description of an embodiment, this description being made with reference to the drawings attached in the appendices, in which:

[0029] FIG. 1 is a schematic illustration of total arterial blood flow, cerebral blood flow, and body blood flow at normal temperatures, with particulate matter in the arterial blood flow;

[0030] FIG. 2 is a schematic illustration of total arterial blood flow, cerebral blood flow, and body blood flow, with particulate matter entering the cerebral blood flow;

[0031] FIG. 3 is a schematic illustration of total arterial blood flow, cerebral blood flow, and body blood flow, with particulate matter entering the body blood flow;

[0032] FIG. 4 is a schematic illustration of total arterial blood flow, cerebral blood flow, and body blood flow, with cerebral to body blood flow reduced by selective brain cooling;

[0033] FIG. 5 is a schematic illustration of total arterial blood flow, cerebral blood flow, and body blood flow, with cerebral to body blood flow reduced by hyperventilation;

[0034] FIG. 6 is a chart depicting one example of the ratio between BBF and CBF changing under different conditions;

[0035] FIG. 7 is a chart describing the mechanisms involved in preventing emboli from reaching the brain and those involved in treating emboli that reach the brain; and

[0036] FIG. 8 is a schematic illustration of the combined effect of cooling the brain and decreasing pC02.

[0037] FIG. 9 depicts a graphical representation of body core temperature and brain temperature in Celsius over time in minutes during a human clinical trial. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0038] In the following detailed description, reference is made to the accompanying drawings, in which are shown exemplary but non-limiting and non-exhaustive embodiments of the invention. These embodiments are described in sufficient detail to enable those having skill in the art to practice the invention, and it is understood that other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the invention is defined only by the appended claims. In the accompanying drawings, like reference numerals refer to like parts throughout the various figures unless otherwise specified.

[0039] Referring to Figure 1, in certain medical procedures, such as cardiac procedures, particulate matter 100 can enter into arterial circulation 106 during surgical and intravascular procedures involving the heart and aorta. Particulate matter may include, but is not restricted to, valve tissue, myocardial tissue, atheroma, calcium deposits, bubbles of gas, and portions of medical devices such as coating materials. Particulate matter may also be referred to herein as particles, embolic material, emboli, debris or bubbles, all of which refer to foreign matter circulating in a blood vessel. When both the body and brain are at normal temperatures, the cerebral brain flow (CBF) 102 and body blood flow (BBF) 104 are at a baseline level. The baseline value of CBF to BBF varies widely between individuals. However a ratio of 1 :5 to 1 :6 is often quoted in the literature for healthy awake adults at rest.

[0040] Referring to Figure 2, the particulate matter 100 may enter into the cerebral blood flow 102. Particles can be observed and counted in a variety of arteries using Doppler ultrasound (high intensity transient signals, or HITS). For example: the number of particles entering the brain can be estimated by counting the number of particles traversing one of the middle cerebral arteries. During such medical procedures the number of particles entering the brain can be in the hundreds to thousands. Any particulate matter than enters into cerebral circulation is undesirable and can cause cerebral ischemia and significant deleterious effects.

[0041] Referring to Figure 3, the most desirable option to handle particulate matter 100 once it has entered into the arterial blood flow 106 is to direct the particles away from the cerebral circulation 102 and into body blood flow 104. Particulate matter that enters into non- cerebral (i.e., body) circulation is usually well tolerated. [0042] Referring to Figure 4, a method of reducing particulate matter introduced into the brain comprises altering the ratio of CBF to BBF to divert particulate matter away from the brain and into non-cerebral circulation. The ratio of CBF to BBF can be altered to any value which achieves the desired clinical effect. For example, the ratio of CBF to BBF can be about 85%, 50%), or 5%o of the baseline ratio. In one embodiment, the BBF comprises about 90%> of the total arterial flow, and the CBF comprises about 10% of the total arterial flow. In another embodiment, the BBF comprises about 95% of the total arterial flow, and the CBF comprises about 5% of the total arterial flow.

[0043] In one embodiment, the ratio of CBF to BBF is altered non-invasively. One way of achieving this is by selectively lowering the temperature of the brain which has the effect of reducing its requirements for blood flow. Using the present methods and devices, the brain can be selectively cooled by achieving and substantially maintaining a desired brain-body temperature gradient (or at least maintaining a desired minimum brain-body temperature gradient). Such an effect permits altering the ratio of CBF to BBF in a safer and more efficient manner than by systemic cooling. As will be discussed in detail with respect to FIG. 9, a synergistic effect is observed when CBF to BBF is altered while selectively cooling the brain to create a brain-body temperature gradient, which can lead to even further efficient and cooling of the brain. It is known in the literature that for every degree Celsius drop in brain temperature brain blood flow decreases by approximately 7%. The temperature of the brain may be lowered by selective cooling of the brain using a non-invasive method. In one particular embodiment, the temperature is lowered by introducing cooled fluid into the aerodigestive tract. "Aerodigestive tract" refers to a complex of organs that, in total, make up the tissues and organs of the upper respiratory tract and the upper part of the digestive tract. The aerodigestive tract, as used herein, is the lips and mouth, tongue, nose, throat, vocal cords, esophagus, stomach and trachea. The aerodigestive tract does not include the lungs or the intestines.

[0044] In addition to altering the ratio of CBF to BBF, reducing the temperature of the brain has other benefits. Clinical studies using animal models have shown that reducing brain temperatures helps preserve the brain during circulatory arrest or at low flow rates by delaying the onset of permanent cellular damage. Furthermore, reduced brain temperature helps prevent and reverse inflammation, and helps prevent and reverse reperfusion injuries, all of which can be caused by emboli in the brain. [0045] Suitable methods and apparatuses for selective brain cooling are disclosed by U.S. Patent No. 8,308,787 B2, entitled Rapid Cooling of Body and/or Brain By Irrigating With A Cooling Liquid, U.S. Patent Publication No. 2013/0030411 Al, entitled Non-Invasive Systems, Devices, and Methods for Selective Brain Cooling, PCT/US2014/043509 entitled Brain Cooling Devices and Methods, and U.S. Provisional Application No. 62/056304 entitled Brain Cooling Devices and Methods, all of which are hereby incorporated by reference in their entirety for all purposes. These devices function by providing cooling fluid to the aerodigestive tract to rapidly cool the brain. Preferably, the blood flow is cooled along the entire path to the brain, or what is referred to as the "long column."

[0046] For example, cooling the brain may be achieved by introducing free-flowing, cool fluid into the aerodigestive tract with one or more tubes (e.g., catheters). The one or more tubes can be single or multiple lumen tubes of a sufficient size to permit a flow of free- flowing cooling fluid through the tubes. Such one or more tubes can be positioned exterior to the nose and/or mouth of a subject; and in some embodiments, such one or more tubes can be inserted into the nose and/or mouth of a subject. For example, in some embodiments, one or more tubes are positioned exterior to or are inserted into the mouth of the subject. In other embodiments, one or more tubes are positioned exterior to or are inserted into the nose of the subject. In still other embodiments, one or more tubes are positioned exterior to or are inserted into the nose and the mouth of the subject. The one or more tubes can comprise one or more outlet ports to deliver cooling fluid to the aerodigestive tract. For example, in some embodiments, cooling fluid can be delivered into the proximal, and/or mid, and/or distal esophagus. Fluid in the aerodigestive tract can passively flow from the nose and/or mouth of a subject and/or can be actively removed through one or more tubes (e.g., through different tubes or through the one or more tubes through which cooling fluid is introduced, such as with a multi- lumen tube).

[0047] An initial temperature of cooling fluid can include various temperatures. For example, the initial temperature of cooling fluid can be in the range of - 30 to 30 °C (e.g., -30 °C, -25 °C, -20 °C, -15 °C, -10 °C, -5 °C, 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, and any value therebetween). In other embodiments, initial temperature of cooling fluid can be higher than 30 °C or lower the -30 °C. Optimal temperature may vary depending on factors, such as body size, procedure type, desired brain-body temperature gradient, and the like. Fluid can be substantially maintained at any temperature (for example, within a range of ± 2 °C) by equilibration with one or more heat exchangers at the desired temperature and/or by adding additional cool fluid or other cold objects (e.g., ice) to the fluid.

[0048] One configuration of a cooling system and method can comprise placement of one or more tubes exterior to or within the mouth and/or nose of a subject to introduce a free- flowing fluid into the aerodigestive tract to selectively cool the brain of the subject. For example, one or more nasal tubes can be inserted into each nostril of the subject, and/or one or more oral tubes can be inserted into the oral cavity of the subject. To help isolate the lungs, an endotracheal tube can be inserted through the mouth into trachea. Further, the endotracheal tube can comprise or be coupled to an inflatable balloon to assist in occluding the trachea. An inflatable balloon - whether esophageal, tracheal, or other - can be inflated with gas (e.g., air) and/or liquid (e.g., water). In some embodiments, the gas and/or liquid can be chilled to a desired temperature to assist in cooling the tissue with which the inflatable balloon is in contact (e.g., and, by effect, cooling blood flowing to the brain). In other embodiments, the gas and/or liquid can be warmed to a desired temperature (e.g., with respect to the irrigation fluid) in order, for example, to improve a contact/interface with surrounding tissue. Inflating a cuff with cooled fluid and/or gas can additionally assist in pre- equilibrating the cuff with the cooling fluid in a subject's aerodigestive tract (e.g., preventing and/or eliminating contraction of the cuff).

[0049] The alteration of the CBF to BBF ratio can be accomplished on a transient, or short- term, basis (i.e., during a short procedure). That is, the alteration of the CBF/BBF only needs to occur while the embolic material is being cleared after it has been dislodged or generated. Thus, if embolic material is generated over a short period of time, the alteration of CBF to BBF may only need to occur for a short period of time. The transient period may vary from about 2-60 minutes, and any duration in between. The temperature differential between the brain temperature and body temperature may be adjusted so that the cerebral blood flow is minimized during periods of high embolic burden. Temperature differentials of between about 0.25 and 20 degrees may be optimal. The methods and apparatus for cooling described in the previous paragraph are well suited for transient cooling, since they are projected to be able to cool a brain at a rate of 0.05 to 1.0 Celsius per minute according to animal studies. Other conventional cooling modalities may also be used, although they are not able to achieve cooling rates which are this rapid. [0050] The alteration of the CBF to BBF ratio can also be accomplished on a continuous basis for longer procedures. That is, if embolic material is dislodged over a relatively lengthy period of time, then the brain may be kept cold on a continual basis at a relatively stable temperature to keep CBF down and reduce the ratio of CBF to BBF.

[0051] External heat may be added to the body to maintain different brain and body temperatures. One method of adding heat to the body is by warming the skin. Warming the skin also has the additional effect of causing skin vasodilation and thereby further increasing the percentage of blood flow to the body vs. the brain. As another example, the core can be warmed by applying heat to the skin of the patient, which can assist in encouraging blood toward the skin and muscle of the patient and, in turn, assist in encouraging embolic material toward the skin and muscle of the patient, rather than toward the brain or other organs (e.g., the kidneys). Thus, actively warming the skin can be beneficial in certain circumstances.

[0052] After the CBF to BBF ratio has been altered to a clinically desired value, any medical procedures which may produce embolic material are carried out. Due to the reduction in the CBF to BBF ratio, the majority of the embolic material is directed to the non- cerebral vasculature, thereby reducing the embolic load on the brain. The CBF to BBF ratio may be continuously adjusted, and may be modulated so that CBF is lowest during the highest periods of embolic burden generated by the medical procedure.

[0053] As seen in Figure 5, another method of altering the CBF to BBF ratio is to manipulate pC0 ₂ through hyperventilation or other methods. For every drop in mmHg of pC0 ₂ there is about a 3% drop in brain blood flow. Decreasing pC0 ₂ is a potent cerebral vasoconstrictor and is commonly used to treat severe traumatic brain injury. It has an extremely rapid onset of action and is easily induced through use of ventilator adjustments (e.g., increasing minute ventilation).

[0054] Reducing brain blood flow using pC0 ₂ can be done alone or in conjunction with selective cooling of the brain. Reducing brain blood flow using pC0 ₂ poses a risk of causing ischemia as it is such a powerful method of reducing brain blood flow that is independent of brain metabolic need. This is unlike reducing blood flow using cooling which does not have a risk of ischemia due to the protective effects of cooling (i.e., reducing brain metabolism). Thus, the dose and duration of hyperventilation therapy is limited in a warm brain. [0055] Brain cooling can enable and potentiate the use of pC0 ₂ levels that are lower than are currently safe in a warm brain through its protective effects including reducing brain metabolism. With brain cooling in place one can safely utilize pC0 ₂ levels from 40 mmHg to 10 mmHg. That is, brain cooling and manipulation of pC0 ₂ produce a synergistic effect. With reference to FIG. 8, when the brain temperature is decreased by cooling the brain, it causes decreased metabolic demand in the brain and a reduction in CBF. The decreased metabolic demand allows a larger manipulation of pC02 without risk of ischemia. The present systems and methods enable such a decrease in the CBF to BBF ratio through selective cooling of the brain (rather than systemic cooling of the brain and body core). A decrease in the CBF to BBF ratio in this manner can lead to even further reduction in brain temperature (and a corresponding increase to the brain-body temperature gradient), as will be described below, which further assists in discouraging embolic materials in the brain and which provides a safer environment for a decreased CBF to BBF ratio.

[0056] Furthermore, the efficiency of selective cooling of the brain utilizing the above- mentioned apparatuses and methods is dependent on the amount of blood flow into the brain. That is, the lower the blood flow, the longer the blood is exposed to the effects of the cooling fluid, and the colder the brain becomes. Therefore, as one reduces pC0 ₂ and decreases blood flow into the brain, there is a decrease in the temperature of the brain. This decreased temperature further protects the brain from decreased blood flow. Therefore, using pC0 ₂ to decrease brain blood flow is significantly safer when used in conjunction with selective cooling.

[0057] The temperature of the cerebral blood flow (and therefore the brain) may be monitored using a jugular blood flow catheter. Readings from the jugular blood flow catheter may be used to control the termination of the cooling treatment (for example the re -warming rate) by adjusting the temperature of the cooling fluid and/or the flow rate of the cooling fluid through the aerodigestive tract. These variables may also be adjusted on the basis of a pre-set schedule.

[0058] If CBF has been further reduced by reducing pC02, one can use the jugular catheter to measure the 02 saturation of the blood as it is exiting the brain and one can determine if the brain is in danger of ischemia due to lack of blood flow (and therefore oxygenation) for any given brain temperature. One can then adjust the pC02 level if necessary to ensure proper oxygenation of the brain. [0059] Referring to Figure 6, the ratio of BBF to CBF is illustrated graphically. As seen there, the baseline ratio of BBF to CBF may be approximately 5: 1, as illustrated by line 602. In order to avoid ischemia, the cerebral blood flow should be maintained over dashed line 604 at a brain temperature of 37°C, and over dashed line 606 at a brain temperature of 30°C. In this example, the ratio of BBF to CBF may be adjusted to over 20: 1 while still remaining over the threshold of ischemia at a brain temperature of 30°C. As shown by line 612, selective cooling combined with C0 ₂ manipulation (e.g., decreasing C0 ₂ , in the embodiment shown) can produce a BBF to CBF of over 20: 1 while still remaining above the threshold of ischemia. Similarly, line 614 representing cooling plus vasodilation results in a BBF to CBF of well over 20: 1. Thus, as compared to baseline, a significantly greater proportion of blood is diverted to the body, thereby diverting embolic particles away from the brain and into the body, where they are better tolerated.

[0060] Referring to Figure 7, a comparison of the projected volume of brain tissue subjected to injury due to embolic material demonstrates two approaches, deflection treatments, and deflection treatments plus pre-ischemic treatments in which this disclosure can protect the brain from injury due to embolic material produced during the procedures noted in the background section. The first column shows a baseline level of ischemia due to embolic material entering the cerebral brain flow. The second column shows the effect of deflection treatments, such as decreasing pC0 ₂ (without cooling), selective cooling of the brain alone, selective cooling of the brain plus warming of the body; and decreasing pC0 ₂ (with cooling). The third column shows the combined effect of deflection treatments plus pre- ischemic treatments. Pre-ischemic treatment refers to cooling of the brain prior to delivery of embolic material. Pre-ischemic treatment of this type has been shown in a variety of animal models to reduce or eliminate ischemic damage caused by interruption of blood flow.

[0061] In another embodiment, methods are described to avoid increasing the CBF. Specifically, hemodilution of the patient should be minimized as there will be less 0 ₂ per unit of blood and therefore the brain's self-regulation methods will automatically increase the CBF to ensure a constant supply of 0 ₂ . Additionally, use of anesthetic compounds that are known to increase CBF, such as halothane, should be minimized on the patient. Additionally, the arterial 0 ₂ saturation should ideally be kept above 95% to ensure sufficient 0 ₂ delivery to the brain to minimize hypoxia driven increase of CBF. Finally, the use of any other agents that increase CBF should be minimized. [0062] In another embodiment, a method of protecting the brain during induced cardiac 'stand-still' (as seen in TAVI and off-pump CABG) is disclosed. This method comprises continuously cooling a long column of blood during the period of stand-still. That is, the nose, pharynx, and esophagus are irrigated with a cold fluid to create a long column of cold blood and tissue. Therefore, when blood flow is re-started, a cold column of blood will enter the brain as the first thing during reperfusion. This long cooling column provides a much larger column of cool blood entering the brain as compared to other methods of selective cooling. As used herein, cardiac stand-still is intended to encompass absolute cardiac standstill (i.e., no blood flow) as well as partial cardiac stand-still where blood flow comprises approximately 10%, 20% or even 30% of normal blood flow.

[0063] In addition to reducing the number of particles entering the brain, it is expected that the methods set forth herein will also reduce the effect of particles that enter into the brain. Animal trials have shown that cold treatment will help prevent ischemia by allowing time for collateral flow to develop, treat ischemia by starting reperfusion (via collaterals or recanalization) with cold blood, and prevent the expansion of ischemia by reducing edema. Very small infarcts may be the easiest to treat, as they rely heavily on microscopic collaterals, and micro-collaterals can start flow in one second.

[0064] FIG. 9 depicts a graphical representation of body core temperature in Celsius measured in the bladder (e.g., the temperature of urine moving though the bladder) and brain temperature in Celsius measured in the jugular bulb (e.g., the temperature of blood leaving the brain through the jugular vein) over time in minutes in a single patient undergoing cardiac surgery during a human clinical trial. Mechanical cardiopulmonary support was initiated at approximately 55 minutes. The temperature of the blood exiting the brain is expected to be slightly warmer than blood temperature entering the brain because the blood is heated by heat generated in the brain; however, the expected difference is believed to be small (e.g., approximately 0.25 degrees Celsius). One embodiment of the present devices was activated at time equals zero minutes, and cooling fluid was introduced into the aerodigestive tract of the patient to begin cooling. As depicted, throughout the clinical trial, body core temperature was observed to decrease at a rate of about 1 degree Celsius per hour. Also as depicted, brain temperature was observed to have three phases, which are represented by approximation with numerals 1, 2, and 3 in FIG. 9. In Phase 1, brain temperature decreased at approximately 16 degrees Celsius per hour with targeted cooling for approximately 15 minutes. Brain cooling is believed to have occurred at a much greater rate than body core cooling due at least in part to, for example, the proximity of the brain in the cycle to cooled blood in the carotid and vertebral arteries and the relatively small size of the brain compared to the body core. For example, brain mass can be approximately 1.5 kilograms compared to a body mass of approximately 100 kilograms (i.e., brain mass can be approximately 1.5% the body mass of a subject); however, the brain receives approximately 15% of cardiac output. This indicates, among other things, that on a per gram basis, the brain receives approximately 10 times more perfusion than the body core and, therefore, when using the present devices and methods, the brain responds to cooling faster than the body core, as demonstrated in the human clinical trial and depicted in FIG. 9.

[0065] As depicted in FIG. 9, Phase 2 of cooling represents a smaller decrease in brain temperature over time, with the temperature differential between brain temperature and body core temperature remaining relatively constant (e.g., approximately 3.5 degrees Celsius throughout Phase 2). In other words, the brain was not observed to cool significantly faster than the body core in Phase 2, but instead, the brain was observed to cool in parallel with the body core, while maintaining the brain-body temperature gradient. This decrease in rate of cooling after rapid initial rates of cooling was observed previously in other human clinical trials using the described devices and methods, as well as in pre-clinical animal trials. Phase 2 brain cooling is believed to have occurred at a smaller rate than Phase 1 brain cooling at least in part to, for example, heat transfer from blood flowing to the brain (e.g., through carotid and vertebral arteries) reaching an equilibrium with tissue cooled with the present devices for a given blood flow rate. As will be discussed below, further decreasing cerebral blood flow rate can enable additional heat to transfer from blood flowing to the brain into surrounding cooled tissues because, for example, blood is in contact with the cooled tissues for a longer period of time. In other words, temperature of blood flowing to the brain (e.g., through the carotid and vertebral arteries) stabilizes as cooling zones around the carotid and vertebral arteries to the brain have fully developed.

[0066] As depicted in FIG. 9, Phase 3 of cooling exhibits a significant increase in rate of brain cooling over time. For reasons unrelated to the present devices and methods, there were difficulties in initiating cardiopulmonary bypass during the clinical trial in this patient, which caused a decrease in blood pressure. The increase in rate of brain cooling occurred while the subject was experiencing this decrease in blood pressure and, therefore, a decrease in cerebral blood flow. The decrease in blood pressure and, therefore, cerebral blood flow is believed to have significantly decreased brain temperature (and increased rate of brain cooling) due at least in part to, for example, blood passing through cooling zones at a slower rate, enabling heat to leave the blood more effectively. No similar decrease in body core temperature (or rate of body core cooling) was observed, which is believed to be a result of the present devices and methods. Once blood pressure returned to its original level, the subject's brain temperature increased.

[0067] The above specification and examples provide a complete description of the structure and use of exemplary embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this invention. As such, the various illustrative embodiments of the present devices are not intended to be limited to the particular forms disclosed. Rather, they include all modifications and alternatives falling within the scope of the claims, and embodiments other than the one shown may include some or all of the features of the depicted embodiment. For example, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0068] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) "means for" or "step for," respectively.