ES2939818T3 - Device to reduce the effects of energy absorption by shaking by reducing blood flow from the skull - Google Patents

Abstract

Venous compression in the neck reduced the extent of axonal injury in a standardized rodent model of mild TBI. The mechanism restricted venous drainage from the brain and increased blood volume and pressure in the central nervous system, thus shifting intracranial physiology to the steep end of the volume compliance curve. Lack of compliance within the confines of the skull and spinal canal prevented energy absorption and resultant axonal injury by causing them to approach a more elastic collision when the skull was struck during the drop weight method. A first embodiment may be a device comprising a means for reducing the absorption of SLOSH energy in a fluid-containing organism by reducing the flow of one or more outflow vessels from the skull by compressing said vessels. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Device to reduce the effects of energy absorption by shaking by reducing blood flow from the skull

CROSS REFERENCE TO RELATED REQUESTS

This patent application claims priority to US Application Serial Number: 12/931,415 filed February 1, 2011, which is a continuation-in-part of US Application Serial Number: 12/807,677 filed September 10, 2010 and entitled “Method to reduce SLOSH energy absorption and its damaging effects through the reduction of inelastic collisions in an organism”, which claimed priority to US Provisional Application Serial Number: 61/241,625 filed on September 11, 2009 and to the US Provisional Application Serial Number: 61/260,313 filed November 11, 2009. This patent application also claims the benefit of priority to US Provisional Application Serial Number: 61/518,117 filed April 28, 2011 .

TECHNICAL FIELD

The present disclosure relates generally to methods and devices for restricting blood flow from the head, thereby reducing shaking energy absorption ("SLOSH") and nerve tissue damage.

BACKGROUND

Traumatic brain injury (TBI) remains one of the most common causes of death and morbidity in people under the age of 45, even in Western societies. In the United States alone, 1.7 million people experience a TBI each year, resulting in an estimated total annual cost of more than $60 billion. Historically, head and brain injury prevention has focused on the use of helmets for external cranial protection. This approach is fundamentally flawed in that, regardless of benefit, helmets have provided benefits only for penetrating brain injuries and major skull fractures. These occur in a very small fraction of head injuries in the civilian setting. Military statistics have shown that even on the battlefield, less than 0.5% of LCTs are caused by a penetrating object. However, both military personnel and athletes are subjected to high speed acceleration-deceleration mechanisms that are not mitigated by helmets and lead to concussive brain injury. In large part, the relative freedom of movement of the human brain within the cranial cavity predisposes to linear and rotational force vectors, with the resulting energy absorption resulting in cellular dysfunction and disruption, sometimes with delayed cell death.

The skull and spinal canal contain only nervous tissue, connective tissue, and fat cells, and its interstitium contains blood and cerebrospinal fluid (CSF). This fluid content does not completely fill the rigid container bounded by the skull and bony spinal canal, leaving a "reserve volume." The change in volume within a container with a given change in pressure is called "compliance." Increases in the volume of the contents of the skull and bony spinal canal, within the range of the reserve volume, occur at low container pressures (due to the high compliance of the system). In the presence of the reserve volume, as seen in a normal physiological state, acceleration in the skull can result in a differential acceleration between the skull and its contents. As a consequence, the brain and fluids collide with each other and with the interior of the skull. Considering the semi-solid properties of a mammalian brain, this effect is called "shaking."

Although hard hats are effective in preventing infrequent penetration or skull fracture, they have little ability to limit the effects of agitation. Thus, mitigating agitation by filling the reserve volume (decreasing compliance) can significantly reduce the tendency for differential movement between the skull and its contents, and between the various contents of the skull. By mitigating the agitation, an accelerating force on the skull would tend to move the skull and its contents in unison, avoiding collisions between the intracranial contents and thus preventing the absorption of kinetic, acoustic, thermal, and vibrational energy from the brain. .

In an attempt to mitigate intracranial agitation it is recognized that the only intracranial compartment that is most susceptible to rapid and reversible change in volume and pressure is the blood space. The easiest and fastest way to increase the blood compartment is to prevent its emptying by mechanically occluding the draining veins in the neck.

Conventional prophylactic measures designed to protect the brain from injury in the event of head trauma have heretofore included only various helmets. Helmets are primarily designed to protect the skull from fractures and penetration injuries, but to a lesser extent from pathological movements of the brain, eg classic concussion. It has been shown that immobilizing the brain within the skull, increasing intracranial blood volume and thus the compliance margin, reduced the neuronal damage produced by a conventional head impact. The automobile analogy would be the difference between putting extra armor on the outside of the car and putting on a seat belt. The additional external armor of the vehicle improves the external integrity of the vehicle but completely ignores the interior compartment in which the passengers they would still be subjected to extreme forces due to rapid differential acceleration. The seat belt greatly reduces these forces since the vehicle and its passengers are now moving in the same direction.

US Patent 2,676,586 discloses a device for preventing pilot unconsciousness during sudden changes in direction of a fast-moving aircraft. The device includes a collar that carries inflatable pads that are positioned such that they are adapted to apply pressure to the veins that carry blood from the head.

US 2010/000548 A1 discloses a pair of pads held against the ramus of a patient to prevent the mandible from slipping back and causing airway obstruction while the patient's neck is hyperextended to also cause the patient's airway remains open.

To date no effective pharmacological treatment for TBI has been discovered.

Although new compounds, such as progesterone, are undergoing clinical trials, the ability to intervene in and mitigate the cascade of secondary TBI injuries is imprecise. Preventive measures against TBI may one day provide some degree of protection, but conceptually so far they have only focused on external forces and factors. There is potential to reduce neuronal damage by administering omega-3 fatty acids, including docosahexaenoic acid (DHA) both prophylactically and after TBI.

SUMMARY

The present invention is defined by the features of the independent claim. Any procedures disclosed below do not form part of the claimed invention.

Traumatic brain injury (TBI) remains a devastating condition for which extracranial protection in the form of helmets has traditionally been used. Although helmets are effective in preventing most devastating intracranial injuries, penetration injuries, and skull fractures, they are limited in their ability to prevent concussion. In this procedure, the internal jugular vein (IJV) is slightly occluded to increase cerebral blood volume and decrease intracranial compliance. This results in reduced differential acceleration between the skull and its contents, a reduced tendency for movement of the brain and fluid within the skull, resulting in less shear and tear forces, and less energy absorption by the contents, giving as a result all this except traumatic axonal and glial injury.

The invention therefore encompasses embodiments of a device for reducing energy absorption by agitation in a human or animal subject by reducing the flow of one or more neck veins by compressing at least one of said vessels, wherein the device comprises a collar configured to only partially encircle the neck of a human or animal subject, and at least one inwardly directed region to contact the neck when encircled by the collar, thereby applying localized pressure to a neck vein.

In some embodiments of this aspect of the disclosure, the at least one inwardly directed region for contacting the neck may be selected from the group consisting of: a protrusion, a shoulder, and a thickened region of the collar, and wherein the protrusion , the shoulder and the thickened area of the collar can be rigid or semi-rigid.

In some embodiments of this aspect of the disclosure, the at least one inwardly directed area for contacting the neck may be arranged in said collar to exert pressure on the area of an internal jugular vein when the neck of a human subject or animal is inserted into said collar.

In some embodiments of this aspect of the disclosure, the collar may be elastic.

In some embodiments of this aspect of the disclosure, the size of the collar and its tension may be adjustable.

In some embodiments of this aspect of the disclosure, the device may further comprise one or more pull-release mechanisms.

In some embodiments of this aspect of the disclosure, the device may further comprise a monitoring device, a recording device, a communication device, or any combination thereof.

Another aspect of the disclosure encompasses embodiments of a method for increasing the intracranial pressure of a human or animal subject comprising: (i) encircling the neck of a human or animal subject with a collar, wherein said collar has at least one directed area inward to come into contact with the neck of a human or animal subject; (ii) locating the at least one inwardly directed area for contact with the neck in a neck area located over a neck vein carrying blood from the subject's intracranial cavity; and (iii) applying pressure to the neck vein by pressing the at least one inwardly directed area to contact the neck on the neck surface, thereby restricting blood flow out of the subject's intracranial cavity, thereby increasing the subject's intracranial pressure and/or volume.

In some embodiments of this aspect of the disclosure, the method may further comprise the step of increasing the pCO2 of the intracranial cavity, thereby reducing the effect of intracranial agitation on the blood of the human or animal subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Additional aspects of the present disclosure will become more readily apparent upon review of the detailed description of its various embodiments, described below, taken in conjunction with the accompanying drawings.

Figure 1 is a graph illustrating the change in intracranial pressure (ICP) as a consequence of IVJ compression, p-value < 0.01.

Figure 2 is a graph illustrating the change in intraocular pressure (IOP) as a consequence of IVY compression, p-value 0.01.

Figure 3 is a graph showing a representative follow-up of the observed physiological change in intracranial pressure (ICP) and intraocular pressure (IOP) over a fifteen minute period caused by application (left arrow) and withdrawal of the compression of the IJV (arrow on the right). It is worth noting the rapid response observed in both ICP and IOP after compression of the IJV, as well as the duration in which these changes are maintained.

Figure 4A is a digital image of corticospinal tracts stained for PPA after injury without application of the IJV compression device in accordance with the disclosure.

Figure 4B is a digital image of corticospinal tracts stained for PPA following injury with application of the IJV compression device in accordance with the disclosure.

Figure 5 is a graph illustrating the effect of IJV compression on axonal injury as indicated by PPA staining, p-value < 001.

Figure 6 is a graph illustrating blood LDH levels in blood samples 0, 1, 12, 24 and 48 hours after exposure to a gas jet. Vials containing 8 mL (control, half-filled) and 16 mL (full) of heparinized blood were subjected to a single 15-mL CO ² stream and one half-filled vial containing 8 mL of heparinized blood was subjected to a single 15-mL stream of CO 2 . CO ² of 15 ml double.

Figure 7 is a graph illustrating blood potassium levels in blood samples 0, 1, 12, 24 and 48 hours after exposure to a gas jet. Vials containing 8 mL (control, half-filled) and 16 mL (full) of heparinized blood were subjected to a single 15-mL CO ² stream and one half-filled vial containing 8 mL of heparinized blood was subjected to a single 15-mL stream of CO 2 . CO ² of 15 ml double.

Figure 8 is a graph illustrating blood methemoglobin levels in blood samples 0, 1, 12, 24 and 48 hours after exposure to the gas jet. Vials containing 8 mL (control, half-filled) and 16 mL (full) of heparinized blood were subjected to a single 15-mL CO ² stream and one half-filled vial containing 8 mL of heparinized blood was subjected to a single 15-mL stream of CO 2 . CO ² of 15 ml double.

The drawings are described in more detail in the description and examples below.

Details of some exemplary embodiments of the methods and systems of the present disclosure are set forth in the description below. Other features, objects, and advantages of the disclosure will be apparent to one skilled in the art upon examination of the following description, drawings, examples, and claims.

DETAILED DESCRIPTION

Before the present disclosure is described in further detail, it should be understood that this disclosure is not limited to the particular embodiments described and, as such, may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present disclosure shall be limited only by the appended claims.

When an interval of values is given, it is understood that each intermediate value, up to one tenth of a unit of the lower limit unless the context clearly indicates otherwise, between the upper and lower limit of that interval and any other value indicated or intermediate in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller intervals may be independently included in the smaller intervals and are also encompassed within the disclosure, subject to any limits specifically excluded in the indicated interval. When the stated range includes one or both of the limits, ranges that exclude either or both of these included limits are also included in the disclosure.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as would be commonly understood by one skilled in the art to which this item pertains. divulgation. Although any procedures and materials similar or equivalent to those described herein may also be used in the practice or testing of the present disclosure, preferred procedures and materials will be described below.

Citation of any publication is for disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to anticipate the date of such publication by virtue of prior disclosure. In addition, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

As will become apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with features of any of the various other embodiments. embodiments without departing from the scope of the present disclosure. Any indicated procedure may be carried out in the indicated order of events or in any other logically possible order.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. These techniques are fully explained in the literature.

It should be noted that, as used in the specification and appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a support" includes a plurality of supports. In this specification and in the claims that follow, reference will be made to a number of terms which will be defined to have the following meanings unless otherwise evident.

As used herein, the following terms have the meanings assigned to them unless otherwise specified. In this disclosure, "comprising", "comprising", "containing", and "having" and the like may have the meaning assigned to them in United States patent law and may mean "includes", "having includes”, and the like; "consisting essentially of" or "consisting essentially of" or the like, when applied to the methods and compositions encompassed by the present disclosure, refer to compositions such as those disclosed herein, but which may contain structural groups, components of composition or additional process steps (or analogues or derivatives thereof as discussed above). However, such additional structural groups, compositional components or process steps, etc., do not materially affect the basic and novel characteristic(s) of the compositions or processes, as compared to those of the corresponding compositions or processes disclosed in the present document. "Consisting essentially of" or "consisting essentially of" or the like, when applied to the processes and compositions encompassed by this disclosure have the meaning assigned under United States patent law and the term is open-ended, allowing for the presence of more than indicated provided that the basic or novel features of that indicated are not changed by the presence of more than indicated, but excludes prior art embodiments.

Description

When a liquid in a reservoir or vessel experiences dynamic acceleration or deceleration, a variety of wave motions will develop in the liquid. The oscillation of a fluid caused by an external force, called “agitation”, occurs in moving containers that contain liquid masses, such as trucks, airplanes and liquid fuel rockets. This shaking effect can be a serious problem in energy absorption, and vehicle stability and control. The present disclosure encompasses methods and apparatus for reducing the effects of agitation in living beings, and in particular in the intracranial areas of the human or animal subject.

The mitigation of damage from collision and shock waves is based for the most part on the principle of energy absorption of containers filled with fluid. As there is more room for fluid movement within a container, more energy can be absorbed (agitation) rather than transmitted through the container. To reduce this energy absorption, we must try to get as close as possible to elastic collisions. Elastic collisions are those that result in no net transfer of energy, primarily acoustic, kinetic, vibrational, or thermal (also denoted as coefficient of restitution (r) which approaches 1.0). Various embodiments described below can locally modify, elevate, or temporarily maintain an altered physiology of an organism to reduce the likelihood of energy absorption by agitation, thereby increasing the coefficient of restitution (r). The coefficient of restitution (r) indicates the variance of an impact object moving away from a full elastic collision (an (r) of 1.0 = no energy transfer). The absorption of energy or shock wave in an organism can be considered as a collision of bodies and therefore be defined by a transfer of energy through elastic or inelastic collisions. Thus, the mechanisms for energy absorption by molecules and biological fluids can be identified and the resulting means of mitigating that absorption can be achieved through various agitation reduction techniques. The dissipation of energy after the shock wave is also enhanced with these techniques.

The effort to reduce the space available for movement of the brain by increasing the volume of blood Cerebral agitation may serve to mitigate traumatic brain injury (TBI), affect red blood cells, or increase orthostatic or gravitational tolerance by mitigating agitation at the cellular level (micro agitation) or at the organ level (macro agitation). Red blood cells (RBCs) or erythrocytes are highly distensible and have a “stirringable” volume to surface area of only 60 percent. Distension or stiffening of these erythrocytes can reduce agitation within individual cells at a cellular level (micro agitation) and thus reduce energy absorption upon collision. The molecules themselves have a three-dimensionality and may lack cross-bridges providing flexible conformational changes that can promote agitation. Various disclosed mechanisms can safely and reversibly modify the conformational state of certain structures, cells and molecules in the circulatory system which will then reduce energy absorption by agitation at the molecular level (molecular agitation).

The concomitant elevation of local CO ² and thus lowering of an organism's pH environment may also serve to mitigate agitation. Elevated inspired CO ² (hypercapnia) can mitigate TBI by reducing macro-stirring within the skull, although it also has the ability to reduce micro-stirring within each individual RBC and to reduce molecular agitation of each individual hemoglobin molecule. Each of these physiological changes allows for better passage of the forces transmitted through the blood and brain tissues with less energy being absorbed. In the more than 150 cc of cerebral blood within the brain there are more than 1012 erythrocytes (1 trillion cells) that hypercapnia can potentiate to more closely approximate the elastic collisions of cells and thus reduce the absorption of collision or wave energy expansive In addition, a state of hypercapnia can also potentiate the collisions of all hemoglobin molecules present in the skull and body for greater elasticity, thus reducing the absorption of shock or collision energy. There are 8 x 1012 GR in the human body, more than a trillion in brain space at any one time. All these cells are susceptible to energy absorption by agitation and this absorption would be reduced when hypercapnia occurs. Furthermore, there are approximately 2.4 x 108 hemoglobin molecules within each RBC. Consequently, there are 1.9 x 1022 hemoglobin molecules that are capable of absorbing the energies of a shock wave. The shaking energy absorption of these molecules can be significantly reduced by hypercapnia by modifying the molecules to more closely approximate elastic collisions.

Hemoglobin is made up of four iron-containing heme components and four globins that surround (envelop) each heme, essentially making it waterproof. If shock wave energies are absorbed by fluids and blood cells, they are preferentially absorbed by hemoglobin which then modifies its conformation to allow water to enter the envelope formed by heme components leading to rapid catalytic oxidation to give methemoglobin and superoxide. Superoxide is oxygen with one extra electron; methemoglobin is merely oxyhemoglobin devoid of a superoxide. Without this extra electron, methemoglobin has no ability to carry or transfer oxygen (thus the brain is starved of oxygen), and in the case of blast injury to the lungs, very large levels of methemoglobin have been reported. Red blood cells can very slowly reduce methemoglobin to functional hemoglobin although if this methemoglobin reductase reaction is unable to divert the proper electrons to oppose this redox-type chemical reaction, the side effect of harmful oxidative superoxide formation, oxide, occurs. nitric, peroxynitrite, etc. Thus, when an electron moves from one molecule to another, the donor molecule is oxidized while the acceptor molecule is reduced (hence the term "redox"). Methylene blue has been used for decades as a safe and well-tolerated antidote for cyanide poisoning (and methemoglobinemias). Safely and dramatically facilitates the reducing pathways of methemoglobin back to hemoglobin.

Hypercapnia not only pushes methylene blue into red blood cells where it can be functional, but also appears to actually cause methemoglobin reductase to more rapidly convert methemoglobin back to hemoglobin. In addition, the antioxidants (electron donors) ascorbic acid (vitamin C) and riboflavin are also delivered to the erythrocyte by hypercapnia; these antioxidants are not useful for energy absorption or subsequent blasting out of erythrocytes. A soldier or athlete can be given physiologic daily doses of vitamin C, riboflavin, and methylene blue (not a vitamin) and when necessary, hypercapnia will drive these cofactors into the erythrocyte where they can blunt the effects of energy absorption from the shock wave.

The present disclosure encompasses embodiments of a process for reducing energy absorption by agitation by reducing inelastic collisions in a fluid-containing organism, wherein the process is one or more of reversibly increasing the pressure or volume within the fluid. organs or cells, or reversibly modify the configuration or rigidity of the cell, molecular or vascular wall within said organism. One embodiment of a procedure to increase the volume and/or pressure within the skull may be temporarily increasing the pCO ² in the body of the organism by changing the fractional percentage of CO ² inspired by the organism or by reducing its CO ² clearance below the production of CO ² by the body. This procedure can maintain the CO2 levels inspired by the previous hypercapnia until they exceed the reference levels. CO ² is actively and instantaneously pumped into erythrocytes, and after the external CO ² supply stops, intracellular CO ² levels may require hours to return to normal. These levels can be achieved and maintained with an externally applied breathing circuit that can modulate the fractional percentage of CO ² inspired by the body or reduce the rate of CO ² elimination below that of CO ² production by the body. The circuit could be one or more of a non-breathing circuit, a breathing circuit mask o A breathing circuit capable of organizing exhaled gas to modulate the fractional percentage of CO ² inspired by the body (a range from 0.05 to 100% could be used) o A net reduction in CO ² elimination below of CO ² production by the body. The circuit may include an adaptive rebreathing circuit whose dead space can be adjusted based on an individual's weight and an estimated tidal volume, and a desired or optimized level of hypercapnia (an increase in pCO ² of at least 2 mmHg per breath would be optimal). above reference levels). The mask or canister may incorporate one or more dead space tubes or channels that provide an overlapping inhalation and exhalation path and thus create a mixture of inspired and expired gases. Alternatively, a fresh gas source, potentially containing ^CO2, can be added when indicated by capnography (end-tidal ^CO2 measurement), if used. A rebreathing breathing circuit may have one or more of the following: a mask or collection container that acts as the interface between the breathing circuit and the breathing passages that has one or multiple channels or tubes whose length or volume can be rapidly adjusted to regulate the amount of dead space containing previously exhaled gas that will be rebreathed by an individual for the express purpose of raising or modulating their local CO ² level within their bloodstream. The circuit may also contain a physiologically insignificant amount of CO ² in communication with a valve for delivery to the patient, a fresh gas reservoir in communication with the fresh gas flow source for receiving fresh gas during exhalation, and a supply of fresh gas. reserve containing CO ² in communication with the outlet through the valve. Alternatively, a non-rebreathing circuit may consist of one or more of the following: a non-rebreathing valve that prevents exhaled gas from the subject from flowing into the circuit, a fresh gas source operative to deliver a fresh gas containing a physiologically insignificant amount of carbon dioxide to the subject via the non-rebreathing valve and a reserved gas source operative to deliver a reserved gas having a predetermined partial pressure of carbon dioxide to the subject, also via from the inspiration port of the non-rebreathing valve.

Venous blood returns to the heart from the muscles and organs partially devoid of oxygen and containing a full amount of carbon dioxide. Blood from various parts of the body is mixed in the heart (mixed venous blood) and pumped to the lungs through the pulmonary artery. In the lungs, blood vessels divide into a network of tiny capillaries that surround tiny lung sacs (alveoli). The vessels surrounding the alveoli provide a large surface area for diffusional gas exchange down their concentration gradients. After inhaling a breath of air into the lungs, it dilutes the CO ² remaining in the alveoli at the end of the exhalation. A concentration gradient is then established between the partial pressure of CO ² (pCO ² ) in the mixed venous blood (pvCO ² ) reaching the alveoli and the alveolar pCO ² . CO ² diffuses into the alveoli from the mixed venous blood from the beginning of inspiration (at which time the concentration gradient for CO ² is established) until an equilibrium is reached between the pCO ² in coming blood of the pulmonary artery and the pCO ² in the alveoli at some point during respiration. The blood then returns to the heart through the pulmonary veins and is pumped to the arterial system by the left ventricle of the heart. The pCO ² in arterial blood, called arterial pCO ² ( ^pa CO ² ), is then the same as in equilibrium with the alveoli. When the subject exhales, the end of their exhalation is considered to come from the alveoli and therefore reflects the equilibrium CO ² concentration between the capillaries and alveoli. The pCO ² in this gas is the pCO ² at the end of exhalation (p ^et CO ² ). Arterial blood also has a pCO ² equal to the pCO ² in equilibrium between the capillaries and alveoli.

With each breath exhaled some CO ² is removed and with each inhalation new air is inhaled which contains very little CO ² (currently 0.04%) and dilutes the residual equilibrated alveolar pCO ² , establishing a new gradient so that CO ² diffuses out of the mixed venous blood into the alveoli. The respiratory rate, or ventilation (V ^e ), usually expressed in l/min, is exactly that required to eliminate the CO ² carried to the lungs and establish a balance between the alveolar PCO ² (p ^a CO ² ) and that of the lungs. arterial blood (PaCO ² ) of approximately 40 mmHg (in normal humans). When more CO ² is produced (for example as a result of fever or exercise), more CO ² is carried into the lungs and more deeply must be breathed in to remove the additional CO ² from the alveoli, thus maintaining the same p ^a CO ² balance, but if CO ² production remains normal, and hyperventilation occurs, then excess CO ² is removed from the alveoli and CO ^{2 pa} decreases. There are many situations in which you want the inspired CO ² to be higher than it would normally be physiologically. This increased CO ² state in the system has many protective benefits. It often results in discomfort proportional to the increase in PaCO ² , however there is a very large safety interval whereby the PaCO ² in the body can be doubled without known harm. When PaCO ² rises sharply to more than approximately 80 mmHg, consciousness may be affected, although this effect is reversible by lowering PaCO ² . Some other deleterious effects are recognized.

One way to contribute to the body's pCO ² levels may be through the administration of one or more drugs known to change the body's pH, such as carbonic anhydrase inhibitors. Some examples of carbonic anhydrase inhibitors are topiramate, methazolamide, dorzolamide, or acetazolamide. Carbonic anhydrase inhibitors can act as mild diuretics by reducing the reabsorption of bicarbonate and NaCl in the proximal tubule of the kidney. Therefore, bicarbonaturia will produce metabolic acidosis. This slight acidosis has many potential benefits in mitigating agitation as described. Anticipated changes in acidic pH that would demonstrate benefit would be between about 7.30 and 7.40.

Another embodiment to raise the pCO ² in the body of an organism can be a respiratory circuit that maintains a high pCÜ ² . A circuit can maintain a pCÜ ² at the end of the estimated and already elevated exhalation by interposing one or several channels or tubes through which the individual breathes, producing a rebreathing of his previously exhaled puff of air. These channels allow inhaled ambient gas and exhaled alveolar gas to mix. The optimal amount of gas to be re-inspired can be determined by estimating the individual's weight in kilograms and multiplying it by a factor, such as 7, to arrive at an estimated tidal volume in cm3. In one embodiment, one third of this volume may be added to the breathing circuit as dead space. This volume determines the expected level of CO ² at the end of exhalation that the device will equilibrate to. Alternatively, an external source of CO ² could be interposed to rapidly increase, and on demand, the percentage of inspired CO ² .

With respect to adding a dead space to increase rebreathing of previously exhaled gas, several thin-walled or paper channels or tubes may extend from the closed nose and mouth portion of the device and/or several zones may be placed sequentially along along the channels or tubes as perforations or points of weakness so that the individual will be able to rip, cut, or break a predetermined amount of the tube and thereby precisely modify the remaining dead space of the circuit. Markings and identifiers placed along the channels/tubes can help the individual decide which perforation or weak area to tear, cut, or remove. Again, they can be determined in the following way: the tidal volume can be estimated by measuring the weight in kilograms and multiplying it by 7, the result would be in cm3 of the tidal volume. To determine the amount of dead space to add to the mask outlet leg, it is only necessary to take the resulting tidal volume and add a corresponding percentage of the tidal volume (eg 33%) to the mask outlet leg. Each incremental increase in dead space added to the exit leg would cause an incremental increase in final pCO ² . For example, if the individual's weight is 120 kg, then the estimated tidal volume would be 840 cm3. It would be desirable for the individual to re-inspire a part of that tidal volume equal to 33% of it, which is equal to 277 cm3. This added volume of dead space is expected to increase pCO ² by approximately 7-8 mmHg.

In addition to adjustable dead space, end-exhalation CO ² monitoring and having the export valve open or closed can be used to modify the source of the next inspired puff in situations where it may be necessary to know precisely the CO ² at the end of the exhalation. For example, if a target end-exhalation CO ² range is 45 mmHg, then after observing that end-exhalation CO ² is only 35 mmHg, the valve would close, requiring the individual to take the next puff from the adjustable dead space tube/reservoir where a puff had previously been inserted. This expiration is typically 4-5% CO ² , allowing for a higher inspired CO ² on the next puff. A tank can act as an intermediate tank to store additional CO ² gas. Although ventilation is increased, the subject breathes accumulated gas with elevated CO ² , allowing pCO ² to rise to the desired level.

A circuit to maintain normal CO ² may include a no-rebreath valve, a fresh gas source, a fresh gas reservoir, and a source of gas for inhalation, such as from the increased dead space zone or a larger reservoir. CO ² concentration. The method of controlling pCO ² in a patient to a predetermined desired level may be provided to comprise a breathing circuit/mask that can increase CO ² to allow an increase in cerebral blood flow and resulting cerebral blood pressure and volume. . With an increase in cerebral blood flow, cerebral blood velocity, and intracranial pressure and volume, there is less space for intracranial tissues to move relative to one another, thereby decreasing brain agitation and pulsatility. This would require minimizing the intracranial volume of the displaceable or compressible tissue/fluid/air structures. Although brain tissue is thought to be incompressible and fluid/blood is also thought to be relatively incompressible, fluids can travel through the vessels and between the skull and spinal canal, allowing back and forth movement of contents within the brain. skull and thus shearing forces between cells, shock forces applied to structures and the absorption of blast wave energies. If elevated CO ² with a resultant increase in cerebral blood volume and/or increased intracranial pressure has been implemented by any means prior to a traumatic event, the brain and its components are less prone to agitation within the skull and relative to each individual component (thus approximating elastic collisions better). Furthermore, if TBI were to occur despite the above restrictive effects of increased cerebral blood flow, even elevated CO ² would serve to optimize the healing environment of the brain tissue itself by reducing the systemic inflammatory response and maximizing the flow of rich hemoglobin. in oxygen which is better able to supply its oxygen due to high CO ² levels by reducing the oxygen affinity of hemoglobin.

The human erythrocyte is highly compliant and, as such, is particularly capable of absorbing energies transmitted to it by undergoing inelastic collisions. Mathematical analysis of Newton's pendulum shows that inelastic collisions absorb energy as acoustic, vibrational, thermal, and kinetic energy, while elastic collisions serve to allow forces to pass through without transmitting as much energy. However, causing an increase in pCO ² in blood and serum (resulting in the erythrocytes pumping CO ² into the cytoplasm), can serve to produce an almost immediate increase in bicarbonate created within the erythrocyte creating a osmotic swelling of fluid in the cell and reducing absorption by agitation. In addition, it has been shown that the walls of erythrocytes that have been exposed to higher levels of CO ² are less compliant; and even in case of swelling, they will facilitate more elastic collisions when forces are transmitted to them. Without wishing to be bound by any theory, it is likely that chloride changes in response to movement of bicarbonate and CO ² also serve to reinforce the conformation of the hemoglobin molecule, reducing the absorption of energy, and thus better mitigating the damage produced by agitation in red blood cells and tissues. Even after the mechanism supplying additional CO ² has been removed, it will take hours for the cells to equilibrate back to pre-hypercapnic levels. This would also serve to reduce the transmission of forces to the brain or any structure with erythrocyte perfusion. The reversible swelling of the cells and the altered compliance of the red blood cell membrane would also serve to reduce the shear thinning capacity that blood typically exhibits and again, this would serve to better approximate elastic collisions when forces are transmitted. .

In addition to increasing the volume within the cell, it is also possible to reversibly modify the vascular, molecular, or cell wall configuration within the organism to reduce energy absorption by agitation. Cell wall configuration can be reversibly modified to increase membrane stability and decrease membrane fluidity. The addition of one or more of DHA and magnesium oxide can be used to modify the configuration of the erythrocyte cell wall. Typical DHA supplements would be on the order of 50-3000 mg orally per day and MgO 50-1000 mg orally per day. The configuration of hemoglobin can also be changed reversibly by changing one or more of the pH (to a pH of approximately 7.0 to 7.5), pCO ² (to a pCO ² of approximately 25 to 80 mmHg), or levels in blood of 2,3-diphosphoglycerate (up to approximately 6.0 to 1000 pmol/ml) within the body to decrease the elasticity and fluidity of hemoglobin. 2,3-Diphosphoglycerate levels can be increased by procedures such as taking phosphate.

Agitation absorption can also be reduced by reversibly increasing the pressure or volume within organs or cells of the body. Intracranial volume and pressure can be reversibly increased by means of a device that reduces the flow of one or several outflow vessels from the skull of said organism. One embodiment of such a device would compress the outflow vessels enough to produce an increase in venous resistance, but not exceed an arterial pressure of approximately 80 mmHg. It is also possible to reversibly increase intracranial volume by increasing arterial blood pCO2 or by administration of one or more medications to facilitate an increase in intracranial volume or pressure including, but not limited to, minocycline, growth factor 1-like to insulin, Provera and vitamin A.

Therefore, one aspect of the disclosure encompasses embodiments of a compression device that when applied to the neck of a human or animal subject reduces the likelihood of energy absorption from the brain by increasing volume and intracranial and intraocular pressure by applying pressure to the outflow vasculature and/or cerebrospinal fluid from the brain. The result would be an increase in the coefficient of restitution (r) of the structure by fixing a strap or collar around the neck of the individual or organism. The compression device can be of any design including, but not limited to, a strap or cord. Such a compression device could preferably be worn before, in anticipation of, and during events with risk of traumatic brain injury and agitation. The compression device of the disclosure further includes at least one protrusion or thickened area of the device that can be positioned over an underlying neck vein to apply localized pressure thereto.

Thus, the collar embodiments of the disclosure comprise a collar that only partially encircles the neck of a human or animal subject, and is sized such that the collar can apply external pressure to areas of the neck located over the internal jugular veins. . It is contemplated that this pressure is due to the internal dimension of the collar being less than the diameter of the neck resulting from the elasticity of the collar. In alternate examples that are not within the scope of the present invention, pressure may be due to the internal dimension of the collar being less than the neck diameter resulting from the collar size alone, or the result of decreasing the internal diameter of the collar. by any procedure such as inflating the collar, an area thereof, or at least a protrusion thereof. External pressure applied to the internal jugular vein will result in a restriction of blood flow through the vein.

Thus, in particular, the collar of the device according to the disclosure includes at least one inwardly directed projection, projection, thickened or expandable zone disposed on the surface of the collar that is proximal to the skin when applied to a neck, to be placed directly over an area of a neck vein. It is contemplated that the at least one protrusion, ridge, thickened or expandable zone may be a fixed ridge or ridge resistant to deformation when pressure is applied to a neck, or may be enlarged by inflation of an inflation device connected thereto. An inflatable protrusion can be placed over a neck vein and then inflated to apply pressure to the underlying blood vessel. Alternatively, the at least one protrusion may not be inflatable but be arranged on an inflatable collar.

It is further contemplated that the collar of the disclosure and/or the inflatable protrusion(s) disposed thereon may be operatively connected to inflation means such as, but not limited to, a powered pump, or a manual compressible pump, with so a liquid, air or a gas can be applied to the collar. In certain embodiments, the collar may further comprise a pressure sensor operatively linked to the inflation means, whereby the degree of inflation of the collar and/or its projection(s) can be regulated with respect to the extent and duration of the pressure. applied to an underlying neck vein.

It is also contemplated that the collar projection(s) of the disclosure may be configured to engage pressure to an area approximately the diameter of an internal jugular vein, greater than that diameter, and may be of any shape that may provide partial restriction of blood flow through the neck vein, including a pointed protrusion, ridge , a thickened area of the collar, and the like.

The compression device can be made of any material including, but not limited to, elastic materials. Elastic materials can be any material that when stretched will attempt to return to the natural state and can include one or more of textile materials, films (woven, non-woven, and netting), foams and rubber (synthetic and natural), polychloroprene (for example Neoprene, trademark), elastane and other polyurethane-polyurea copolymers (for example Spandex, trademark, Lycra, trademark), fiber veil, warp knitted fabrics or narrow stretch textile materials, raschel fabrics, knits, woven type Milanese, satin, twill, nylon, cotton tweed, yarn, rayon, polyester, leather, canvas, polyurethane, rubber materials, elastomers, and vinyl. There are also various elastic materials that are breathable or moisture wicking that may be preferable during extended periods of wear or when worn during periods of exercise. Furthermore the compression device can be partially constructed, coated or constructed from one or more protective materials such as Kevlar (synthetic para-aramid fibers), Dyneema (ultra-high molecular weight polyethylene), ceramics or shear bulk fluids.

The device can circumferentially span the entire neck or only partially the neck, still providing partial or total occlusion of one or more of the outflow vessels in the neck, specifically, but not limited to, the internal and external jugular veins, the veins vertebral and cerebrospinal circulation. The device can horizontally span the entire neck or only part of the upper and lower neck.

One embodiment of the compression device may be preformed for the user with a circular construction. This unique style may have a typed cinch that allows the device to fit any neck size. Alternatively, the compression device may have a first end and a second end connected with a fastener. A fastener can be a hook and step fastener, a hook and loop fastener, a snap fit, a button, or any of a number of fastening mechanisms that would be known to one skilled in the art. A compression device with a fixator could have a pull-away mechanism, whereby the device can be opened or pulled apart with a predetermined force to prevent the collar from inadvertently snagging or applying excessive compression. A quick release or self release embodiment would be the application of small amounts of hook and step type attachments within the circumferential ring which would separate after excessive force was applied to the compression device. Another embodiment of the device could feature an attachment so that the user could pull on one end of the collar (such as a choke collar for a dog) and the force exerted by the user would effectively decrease the length or circumference of the device. When the desired neck compression is no longer needed (such as between football games), then the user could release the compression by a second light traction or by a separate release mechanism also located on the device.

In yet another embodiment of the collar device of the disclosure, the projections capable of applying compressive pressure to an internal jugular vein are compressible pads or solid shapes sized to apply pressure substantially only to the internal jugular vein. It is contemplated that at least one rigid pad or shape may be connected to one or both opposite ends of a resilient arcuate connector that conforms to a predetermined configuration such that the opposite ends of the connector can be displaced to allow the pad(s) or shapes to move. rigid on it are arranged over the neck to apply pressure to the underlying internal jugular vein.

The compression device may have one or more protrusions, or otherwise not be of constant thickness or width. Such an embodiment may have thicker protrusions for alignment with the internal jugular veins to preferentially apply compressive pressure to these veins when tightening the collar. Another embodiment may use inflatable protrusions as will be further described below.

The compression device may also have one or more attached or integrated monitoring, recording and/or communication devices. One such embodiment of the invention would be to integrate a transceiver and/or receiver to allow communications between soldiers on a battlefield or even between coaches and players. In addition, cardiac monitors could include heart rate monitors or cardiac plethysmography that could provide real-time assessment of cardiac physiology while the compression device is in place.

The compression device may also have a cavity or bag attached depending on the height of the compression device used. Obviously, advertising can be printed on the device or decorated therewith. Such an embodiment of the invention would have a larger segment of the collar on which to imprint a trade design or mark.

Another means of restricting blood flow within the neck vasculature would be to incorporate one or more inflatable chamber segments within the collar to modify the circumference or pressure exerted by the collar. One such embodiment could utilize a bulb pump in connection with the chambers, whereby the user would compress the bulb one or more times until the desired air or fluid pressure is retained within the collar chamber.

Another embodiment may use gas or pressurized fluid connected to the chambers. Another embodiment would have a pressure relief valve in communication with the chambers so that once a predetermined pressure within the chamber is reached, any successive pumping action would simply divert the air or fluid pressure to ambient air or the pump itself would simply no longer exist. it would not inflate (an existing correlated example would be the historic “Reebok pump”). An embodiment with a pressure relief valve could prevent over-inflation of the chambers and allow a very precise degree of pressure delivery to the vasculature.

The safe and reversible increase in cerebral blood volume by an amount up to 10 cm3 and pressure by an amount up to 70 mmHg would serve to fill the capacity of the cerebrovascular tree and thus reduce the ability to absorb external energy through energy absorption by agitation. With the application of a measured pressure to the neck, the cranial blood volume increases rapidly and stabilizes at a new higher level. Moyer et al. ((1954) Applied Physiol. 7: 245) indicated that cerebral arterial blood flow was not affected by obstruction of venous blood outflow from the brain. The venous pressure-blood volume relationship shows a decreasing increase in volume as neck pressure increases over the range of 40 to 70 mmHg. Cranial blood volume increases 10 to 30 percent with this neck pressure (Kitano et al., (1964) J. Nuc. Med. 5: 613-625). Cerebrospinal fluid pressure responds to compression of the individual jugular veins. Jugular compression increases cerebral blood flow to a new level in just 0.5 seconds (Kitano et al., (1964) J. Nuc. Med. 5: 616; Gilland et al., (1969) Am. J. Roet. 106: 369).

This degree of increase in cranial blood volume and pressure is advantageous in mitigating agitation. Although minor increases in volume and cranial pressure may still have beneficial effects, an increase of 3 cm3 in volume and 5 mmHg is a gold standard. However, if the pressure is distributed over the length of the veins, much less pressure, eg as little as 1-10 mmHg, is sufficient to increase the resistance to flow in the veins.

The safety of such a venous compression procedure reflects the Queckenstedt maneuver of over 100 years. In this maneuver “neck compression does not interfere with arterial flow to the skull. Although jugular venous flow under the sphygmomanometer may be temporarily stopped, venous outflow from the skull is never completely stopped, particularly because of the incompressible spinal vein–basilar plexus anastomosis and occipital sinuses. (Batson 0. V., (1944) Fed. Proc. 3: 139; Gregg & Andshipley (1944) Fed. Proc. 3: 144). In fact, there was no correlation between electroencephalogram (EEG) changes or changes in systolic arterial blood pressure that occur during jugular compression. Therefore, neck compression of up to 70 mmHg does not affect cardiac output, arteriolar blood pressure, pulse rate, or urine flow.

Therefore, one aspect of the disclosure encompasses embodiments of a device for reducing energy absorption by agitation in a human or animal subject by reducing the flow of one or more neck veins by compressing at least one of said vessels, wherein the device it comprises a collar configured to only partially encircle the neck of a human or animal subject, and at least one inwardly directed area to contact the neck when encircled by the collar, thereby applying localized pressure to a neck vein.

In some embodiments of this aspect of the disclosure, the at least one inwardly directed region for contacting the neck may be selected from the group consisting of: a protrusion, a shoulder, and a thickened region of the collar, and wherein the protrusion , the shoulder and the thickened area of the collar can be rigid or semi-rigid.

In some embodiments of this aspect of the disclosure, the at least one inwardly directed area for contacting the neck may be arranged in said collar to exert pressure on the area of an internal jugular vein when the neck of a human subject or animal is inserted into said collar.

In some embodiments of this aspect of the disclosure, the collar may be elastic.

In some embodiments of this aspect of the disclosure, the size of the collar and its tension may be adjustable.

In some embodiments of this aspect of the disclosure, the device may further comprise one or more pull-release mechanisms.

In some embodiments of this aspect of the disclosure, the device may further comprise a monitoring device, a recording device, a communication device, or any combination thereof.

In some embodiments of this aspect of the disclosure, the device may further comprise a compressible pad or rigid form sized to apply pressure substantially only to an internal jugular vein when disposed against the surface of the neck, said pad or form being disposed in one end of a resilient bow connector.

In some embodiments of this aspect of the disclosure, the device may further comprise a plurality of compressible pads or rigid shapes sized to apply pressure to substantially only one internal jugular vein, wherein at least one pad or shape is disposed at each opposite end of the device. resilient bow connector.

Another aspect of the disclosure encompasses embodiments of a method for increasing the intracranial pressure of a human or animal subject comprising: (i) encircling the neck of a human or animal subject with a collar, wherein said collar has at least one directed area inward to come into contact with the neck of a human or animal subject; (ii) locating the at least one inwardly directed area for contact with the neck in a neck area located over a neck vein carrying blood from the subject's intracranial cavity; and (iii) applying pressure to the neck vein by pressing the at least one inwardly directed area to contact the neck on the neck surface, thereby restricting blood flow out of the subject's intracranial cavity, thereby increasing the intracranial pressure of the subject.

In some embodiments of this aspect of the disclosure, the method may further comprise the step of increasing the pCO ² of the intracranial cavity, thereby reducing the effect of intracranial agitation on the blood of the human or animal subject.

In some embodiments of this aspect of the disclosure, the method may further comprise applying to the human or animal subject a device configured to receive exhaled air from the subject and to recirculate the exhaled air back to the subject, thereby increasing the pCO ² of the intracranial cavity.

In some embodiments of this aspect of the disclosure, the device configured to receive exhaled air from the subject and to recirculate the exhaled air back to the subject may comprise a CO ² source and means for supplying the CO ² to the inhaled air. of the subject.

In some embodiments of this aspect of the disclosure, the method may further comprise increasing the concentration of CO ² in the subject's inhaled air by providing an external supply of CO ² to the subject's recirculated air.

The following examples are set forth to provide those skilled in the art with a complete disclosure and description of how to perform the procedures and use the compositions and compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (eg amounts, temperature, etc.), although some errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, temperature is in °C, and pressure is or near atmospheric pressure. Standard temperature and pressure are defined as 20 °C and 1 atmosphere (1 bar).

It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in range form. It will be understood that such an interval form is used for the sake of convenience and brevity, and therefore it will be interpreted in a flexible manner including not only the numerical values explicitly indicated as the limits of the interval, but also including all individual numerical values or subintervals. within that range as if each numeric value and subrange were explicitly stated. By way of illustration, a concentration range of "about 0.1% to about 5%" will be construed to include not only the explicitly stated concentration of about 0.1% by weight to about 5% by weight, but also includes individual concentrations (for example, 1%, 2%, 3%, and 4%) and subranges (for example, 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range. The term "approximately" may include ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%, or more than or the numeric values being modified.

EXAMPLES

Example 1

Materials and procedures: Two groups of ten (total of 20) male Sprague-Dawley rats weighing between 350 and 400 grams were used. Animals were in 12-h light/12-h dark conditions with rat chow and water available ad libitum.

Rat model of Marmarou impact acceleration injury: anesthesia was induced and maintained with isoflurane using a modified medical anesthesia machine. Body temperature was monitored during the approximately 10-min procedures using a homeothermic electric blanket with rectal probe, and adequate sedation was confirmed by assessing the response to Achilles tendon puncture. Animals were shaved and sterilely prepared for surgery, following a subcutaneous injection of 1% lidocaine local anesthetic into the planned incision site. A 3 cm midline scalp incision was made and the periosteal membranes were separated exposing the bregma and lambda points. A 10 mm diameter, 3 mm thick metal disk was fixed to the skull with cyanoacrylate and centered between the bregma and lambda points.

The animal was placed in the prone position on a foam bed with the metal disc directly below a plexiglass tube. A 450 g brass weight was dropped once through the tube from a height of 2 meters, striking the disk. The animal was then ventilated with 100% oxygen while the skull was inspected, the disc was removed, and the incision was repaired. When the animal regained spontaneous respirations, the anesthesia was discontinued and the animal returned to its cage for post-surgical observation. Buprenorphine was used for postoperative analgesia.

Example 2

Experimental protocol: This work involved two groups, each consisting of 10 animals for a total of 20 animals. Two groups were used, a control lesion group and an experimental lesion group. In the experimental lesion group, rats were fitted with a 15mm size collar, two compression cords being designed to sit over the IJVs and tightened enough to provide slight compression of the veins without compromising the airway. The collar was then fixed around the circumference with a Velcro fastener. The collar was left in place for three minutes before the experimental brain lesion was induced.

Evaluation of intracranial pressure (ICP) measurement in intracranial reserve volume: ICP was measured in five animals using the FOP-MIV pressure sensor (FISO Technologies, Quebec, Canada) as described by Chavko, et al. The rat's head was shaved and sterilely prepared for surgery. The rat was fixed in a stereotaxic apparatus (Model 962; Dual Ultra-precision Small Animal Stereotaxic Instrument, Kopf Instruments, Germany) and a 3 cm midline scalp incision was made. The periosteal membranes were separated exposing the bregma and lambda points. A 2 mm hole was drilled 0.9 mm caudal from the bregma point and 1.5 mm from the midline. The fiberoptic probe was then inserted to a depth of 3 mm into the brain parenchyma.

Infraocular pressure ( IOP) measurement: IOP was measured in all animals using the TonoLab rebound tonometer (Colonial Medical Supply, Franconia, NH) as described in the literature. IOP measurements were taken after induction of anesthesia in all animals and a second time in the experimental group after application of the novel VYI compression device. Following application of the IJV compression device in the experimental lesion group, IOP readings were taken every 30 s while the compression device was in place. Tissue preparation and immunohistochemical labeling: 7 days post-injury all animals (n=20) were anesthetized and immediately transcardiac perfused with 200 mL of cold 0.9% saline was performed to remove all blood. This was followed by an infusion of 4% paraformaldehyde in Millings buffer for 40 minutes. The entire brain, brainstem, and rostral spinal cord were removed and immediately placed in 4% paraformaldehyde for 24 hours. After 24-hour fixation, the brain was blocked by cutting the brainstem above the pons, cutting the cerebellar peduncles, and then making sagittal cuts lateral to the pyramids. The resulting tissue, containing the corticospinal tracts and areas of the medial lemnisci that previously showed traumatically injured axons, was then cut sagittally on a vibratome into sections 50 micron thick.

Tissue was subjected to temperature controlled microwave antigen retrieval using techniques described above. Tissue was preincubated in a solution containing 10% normal serum and 0.2% Triton X in phosphate-buffered saline for 40 minutes. For amyloid precursor protein (APP) labeling, tissue was incubated in rabbit-generated polyclonal antibody against ASF beta (#51-2700, Zymed, Inc., San Francisco, CA) at a dilution of 1:200. in 1% normal goat serum in phosphate buffered saline overnight. Following incubation in primary antibody, tissue was washed 3 times in 1% normal goat serum in phosphate-buffered saline, then incubated in Alexa 488 fluorophore-conjugated secondary anti-rabbit IgG antibody (Molecular Probes, Eugene, OR), diluted 1:200 for two hours. The tissue was subjected to a final wash in 0.1 M phosphate buffer and then mounted using a fluorescence decay preventer and covered. Slides were sealed with acrylic and stored in the dark in a laboratory refrigerator.

Fluorescent microscopy and image analysis: Tissue was examined and images were obtained using an Olympus AX70 fluorescence microscopy system (Olympus; Tokyo, Japan). Ten digital images of tissue from each animal were obtained and then the images were randomized. Individual injured axons were counted independently and the data stored in a spreadsheet (Microsoft Corp., Redmond, WA). Differences between group means were determined using pairwise t-tests and were considered significant if the probability value was less than 0.05. Stereological quantification of axonal injury: A stereological procedure was used to determine an unbiased estimate of the number of PPA-positive axons per cubic mm in the corticospinal tract and medial lemniscus. The optical fractionator technique was performed using a Stereoinvestigator 9.0 (MBF Bioscience, Inc., Williston, VT) and an Olympus AX70 microscope with 4x and 40x objectives. Sagittal PPA-stained specimens were examined at low magnification and regions of interest were drawn incorporating the corticospinal tract and medial lemniscus. The software then randomly selected 50 µm counting frames with a depth of 15 µm and PPA-positive axons were marked. The volume of the region of interest (ROI) was determined using the Cavalieri procedure, the volume of the sum of the counting frames was calculated, the total sum of injured axons within the counting frames was calculated, and an estimate was calculated. of the number of PPA-positive axons per cubic mm.

Example 3

Intracranial reserve assessment

Intracranial pressure volume ( ICP) measurement: ICP was assessed before and after application of the IJV compression device. The reference ICP was 10.23 ± 1.68 mmHg and increased to 16.63 ± 2.00 mmHg after compression of the IVY (figure 1: p<0.01). Notably, this more than 30% increase from baseline occurred within seconds of VYI compression. Intraocular pressure (IOP) measurement: IOP measurements were taken before and after application of the IJV compression device, similar to ICP recordings. The baseline IOP was 11.18 ± 2.27 mmHg and rose to 16.27+ 3.20 mmHg after IVJ compression (figure 2: p<0.01).

The observed 31% increase in IOP after IVY compression is strikingly similar to that observed in ICP after IVY compression, both in magnitude and in rapidity of response (Figure 3).

LCT-impact acceleration model: none of the animals died from head trauma. The animals tolerated the application of the collar without any inappropriate effects observed during the experiment. Specifically, there were no overt or visible signs of discomfort, intolerance, or respiratory distress. All recovered without any complications and displayed normal behavior and feeding habits until the day they were euthanized. At autopsy, the appearance of the brains was mostly normal.

Stereological analysis of PPA-positive axons: To determine the density of injured axons in the corticospinal tracts and medial lemnisci, the stereological optical fractionator procedure was used. Compared with the normal anatomy found in previous experiments with sham animals, control animals without the collar showed focal PPA labeling in many inflamed contiguous and terminal axon segments, consistent with impaired axoplasmic transport in traumatic axonal injury. Following acquisition of digital microscope images of multiple areas within the corticospinal tract and medial lemnisci of multiple sheets of tissue, PPA-positive axon counts in animals receiving the VYI compression collar demonstrated significantly fewer PPA-positive axons. , at a much more similar frequency to sham animals, compared to those subjected to injury without IJV compression (Figures 4A and 4B). These abnormal axons showed typical morphological characteristics of traumatic injury, mainly inflammation and disconnection. By qualitative analysis, the experimental group showed (m sd) 13,540 9808 versus 77,474 25,325 (p<0.01) PPA-positive axons/mm3 in the control group (Figure 5).

Example 4

Two groups of 10 adult male Sprague-Dawley rats were subjected to impact acceleration traumatic brain injury. Before injury, the experimental group was fitted with a 15-mm size cervical collar, which had two compression cords over the internal jugular veins (IJVs). The control group had only the experimental lesion. Intracranial pressure (ICP) and intraocular pressure (IOP) were measured before and after IJV compression to assess the efficacy of the collar. All rats were sacrificed after a 7-day recovery period and brainstem white matter tracts were subjected to fluorescent immunohistochemical processing and labeling of beta-amyloid precursor protein (APP), a marker of axonal injury. Statistical analysis and digital imaging were used to determine if compression of the IVY resulted in a decrease in the number of injured axons.

Example 5

All the animals survived the experimental method and no adverse reactions were observed after the application of the collar. In the experimental group, compression of the IJV resulted in an immediate and reversible elevation of ICP and IOP, by approximately 30%, demonstrating physiological changes secondary to the application of the collar. In particular, the quantitative analysis showed 13,540 PPA-positive axons in the experimental group versus 77,474 in the control group (p<0.0), a remarkable reduction of more than 80%.

Using a standard acceleration-deceleration impact laboratory model of mild TBI demonstrated a reduction in axonal injury following IJV compression as indicated by PPA immunohistochemical staining. Compression of the IJV reduces brain injury from agitation by increasing intracranial blood volume and reducing compliance and the potential for movement of the brain within the confines of the skull.

Example 6

Internal versus external brain protection: compression of the IJV for 3 minutes prior to head trauma led to physiologic alterations in intracranial compliance, as reflected by moderate increases in ICP and IOP, while at the same time and of The pathologic rate of primary neuronal injury is markedly reduced in the standardized rat model of TBI. The reduction in the distensibility of the brain volume could prevent the differential movements between the skull and the brain that lead to energy absorption and primary and secondary neuronal injuries. These pathological changes include axonal tears that disrupt axoplasmic transport resulting in axonal inflammation and activation of apoptotic cascades, as reflected in this model by a statistically significant reduction in PPP counts of injured axons.

In the animal model of the present disclosure, collar application increased ICP and IOP by 30% and 31%, respectively. The effect of compression of the jugular veins on ICP is well known from a clinical point of view. The Queckenstedt test is used to indicate the continuity of CSF between the skull and the head. spinal cord. In this test, ICP is increased by compression of the IJV while CSF pressure is measured in the spinal cord through a lumbar puncture. Increases in ICP have also been shown to occur with the placement of tightly fitting neck stabilization collars that are likely to compress the IJVs. Compression of the IVJ, which can occur when wearing shirts with tight collars or tight ties, has also been shown to increase IOP. In particular, only a slight compressive pressure is necessary to partially occlude the IJVs since it is a low-pressure system. As cerebral artery inflow continues after partial cerebral venous outflow obstruction, intracerebral and venous pressure increases until jugular venous resistance is overcome or blood drainage is redirected to other venous channels. In any case, there is a reduction in intracranial compliance and a moderate increase in ICP.

The immunohistological assay used in the studies of the present disclosure is specific for axonal damage and results in a reliable range of measurable damaged neurons. In addition, the Marmarou model of acceleration-deceleration injury is a well-known and accepted methodology with which to quantify the extent of TBI. The reduction in damaged axons, as reflected by a marked reduction in PPA counts, in the experimental group with the VYI compression device is highly statistically significant (p<0.01). Additionally, the change in ICP was measured after applying the collar in five rats. The results showed that each study rat had a greater than 95% reduction in axonal injury at the confidence interval of the control group.

Claims (7)

1. Collar device for use in a procedure to mitigate traumatic brain injury in a subject by reducing blood flow through one or more veins in the neck, wherein the collar device is configured to be worn by the subject to encircle only partially the subject's neck, and has at least one inwardly directed area configured to contact the neck, thereby applying localized pressure to one or more neck veins prior to and during traumatic brain injury risk events where the pressure is due to the internal dimension of the collar device being less than the diameter of the neck as a result of the elasticity of the collar device. The collar device for the use of claim 1, wherein the at least one inwardly directed area is selected from the group consisting of a projection, a shoulder and a thickened area. The collar device for the use of any one of claims 1-2, wherein the one or more neck veins include the internal jugular vein or the external jugular vein. Collar device for the use of any one of claims 1-3, wherein the at least one inwardly directed area is rigid. Collar device for the use of any one of claims 1-3, wherein the at least one inwardly directed area is a projection. The collar device for the use of any one of claims 1-3, wherein the collar device is elastic. The collar device for the use of any one of claims 1-3, wherein the collar device has a collar size and tension that are adjustable.