Patent Abstract:
deep venous thombosis with the attendant risk of pulmonary embolism and post phlebitic syndrome is a frequent complication in older patients who have undergone surgery , suffered trauma or who have serious illness such as malignancy or sepsis . in any category patients who are 40 years of age or older are considered to be at greatest risk . deep vein thrombi vary from a few millimeters in length to long tubular masses that partially or completely fill the deep main veins of the leg . these thrombi start as small nidi and initially grow in size by deposition of successive red and white layers . the white layers are rich in platelets and neutrophils interspersed with fibrin while the red layers contain most erythrocytes entrapped in fibrin . beyond a certain stage of growth venous thrombi become mostly red , resembling clotted blood , i . e ., the bulk of a clinically significant thrombus is composed mostly of erythrocytes entrapped in fibrin . thus , platelets , neutrophils and especially blood coagulation all contribute to formation of thrombi in deep leg veins . both initiation and propagation of thrombi depend on processes that are necessary for defense of the body against trauma and infection . platelet activation and blood coagulation are necessary to stop the loss of blood from disrupted blood vessels . neutrophil response to stimulation is essential for defense of the body against infection . thus , initiation and propagation of dvt might be considered to represent an undesirably large response of normal defense mechanisms in the deep veins of the leg . approaches to preventing dvt must be based on a realization that neither of these processes can be completely inhibited throughout the body for more than a brief time without serious risk of bleeding or infection . thus it is obviously desirable to inhibit thrombotic processes locally rather than systemically . to do this it will be necessary to obtain higher levels of antithrombotic drugs in the deep veins of the legs than in the systemic circulation . the present patent application proposes devices and methods that will make this possible for the first time . the claims can be considered in two categories . the first is devices necessary to achieve such delivery . the second is a method for delivery of a high level of antithrombotic drugs .

Detailed Description:
ii . proposed new approaches for preventing and treating deep vein thrombosis the current application describes a preferred embodiment for preventing development of dvt and for treating patients who do develop this complication . the preferred embodiment includes a novel method of administering drugs that prevent dvt from forming or preventing the extension of those that have formed . standard heparin is currently the only agent approved for such use in the united states . however , approval of low molecular weight heparin is expected soon . other anticoagulants such as thrombin receptor analogs , boroarginine peptides and hirulogs show promise and could be administered by the same route . analogues of selectins that inhibit neutrophil , platelet and endothelial adhesive receptors are another group of new and potentially useful agents . these also could be administered by the novel route proposed in this application . the preferred embodiment for means of administration of these inhibitors into the foot are described below and form the basis of this patent application . the preferred embodiment for new means of administering anti - thrombotic agents would provide a higher concentration in the deep veins of the legs than in the systemic circulation . the preferred embodiment is based on the essential characteristics of the processes involved : 1 ) the localization of the thrombotic process to deep veins of the legs ; 2 ) the complexity of blood clotting and cellular interactions involved and 3 ) the necessity for these body defense mechanisms to retain some degree of function systemically . it also takes into account the facts that blood clotting and cellular interactions can be inhibited in a dose dependent fashion and that a higher level of anticoagulation is more effective but causes more hemorraghic complications . since venous thrombosis is localized to deep veins in the legs and since blood clotting and cellular interactions can be inhibited by several agents in a dose dependent manner , it is intuitively obvious that maintaining a higher level of inhibitor in the leg veins than in the general circulation would allow the degree of inhibition to be greater locally than systemically . this would provide an opportunity to prevent or retard development of thrombi in deep veins while lowering the risk of bleeding or infection systemically . the preferred embodiment for prevention and treatment of dvt introduces the administration of heparin or other inhibitors into the foot in such a way that the agent goes into the deep leg veins , thereby providing a higher concentration of inhibitor in these veins than would be found in the systemic blood . heparin or other inhibitors would be administered by continuous intravenous infusion or by subcutaneous injection into sites in the foot while the superficial venous and lymphatic systems of the lower leg are collapsed . the simplest way to direct heparin or other inhibitory agent into the deep veins of the legs would be by pressure tourniquet or by pressure boots . extensive venography has shown that contrast dye injected into a vein on the dorsum of the foot is directed into the deep vein on the dorsum of the foot is directed into the deep veins of the leg when sufficient pressure is applied to the leg to collapse the superficial veins . it was estimated that the concentration of material in the leg veins was as much as 100 fold higher than that in the general circulation . this indicates that heparin or other antithrombotic drugs injected into the foot would also be directed into the deep leg veins when sufficient pressure is applied to collapse the superficial leg veins . a similar magnitude of concentration of heparin or other inhibitor in leg vein blood as compared to the general circulation can be expected . iii . devices for compression of superficial veins in foot and calf compression of the superficial veins of the foot and calf will shift the blood that normally flows in these veins to the deep veins of the calf since reduced blood flow in the deep veins of the calf is accepted as a contributing factor in the development of dvt , increasing the blood flow is an accepted means of reducing the risk ( see background for description and documentation ). compressing the superficial veins and shifting blood flow to the deep veins of the calf is an essential element of the proposed new method for preventing or treating dvt . the preferred embodiment of preventing or treating dvt provides a means for obtaining a local high concentration of antithrombotic drugs in the deep veins of the calf of the leg . these deep veins ( see fig1 ) of the calf and are the sites for initiation of dvt in most cases ( see background ). these veins are the soleal , peroneal and tibial plexes . a high local level of antithrobotic drugs will be obtained by administration into a superficial vein on the dorsum of the foot to the deep veins in the calf it will be necessary to have a means of compressing the superficial veins so that the drugs are shunted into the deep veins by the superficial to deep venous communicating veins ( fig1 ). for this gentle controlled , uniform pressure will be applied to the foot and if desired a uniform or graded pressure to the calf of the leg . administration of antithrombotic drugs will need to be continued at least for many hours and in some cases for several days . for this , a specially constructed device will have multiple clinical applications other than delivery of antithrombotic drugs . all embodiments of the air inflatable ( see fig2 ) and the elastic strap / strip devices will be useful in routine ascending venography . they will increase patient comfort during the procedure by replacing the narrow tight tourniquet that is now used . they will reduce the painful post - venography sequella by preventing prolonged retention of contrast material in the superficial veins . lingering intravenous contrast causes endothelial irritation resulting in phlebitis in the foot and leg . this troublesome condition is associated with erythema , pain , tenderness , swelling and localized hyperthermia in the area distal to the type of tourniquet currently in use . this post - injection reaction of iodine contrast for venography can occasionally lead to extension into ascending deep venous thrombosis and , most commonly , troublesome long - term symptomatic superficial venous fibrosis and smoldering inflammatory activity of the veins of the dorsum of the foot . the case of the application of this invention as an aid to clinical venography , its design will alleviate stasis of contrast , subsequent to injection , and its associated sequella , namely regional superficial stasis phlebitis in the foot and distal leg caused by lingering intravenous contrast and the venous endothelial irritation and reaction in the region of the injection reaction . this troublesome condition is associated with erythema , pain , tenderness , swelling and localized hyperthermia in the area distal to the type of tourniquet currently in use which techniques do not provide gentle , consistent , thorough regional superficial venous compression , as is well known in the art . this post - injection reaction of iodine contrast for venography can occasionally also lead to subsequent extension into ascending deep venous thrombosis and , most commonly , troublesome long - term symptomatic superficial venous fibrosis and smoldering inflammatory activity of the veins of the dorsum of the foot . in paralyzed and other patients who require long - term care these devices can be used with convenience and patient comfort . we know of no prior or existing art , which offers the advantages of user convenience and inexpensive construction for obtaining a specified level of pressure and a high degree of patient comfort . these devices will be made in a short ( above the ankle , i . e ., supramalleolar level ) and a long ( just below the knee ) version to meet the needs of different clinical situations . both versions ( embodiments ) will be made in small , medium and large to accommodate the large range of sizes the feet and legs of patients . both embodiments will be constructed with an outer and an inner layer , described below . both the short and long embodiments will have a port to provide access to the dorsum of the foot . because the size of the foot and the pattern of superficial veins will vary among patients , the port will be sufficiently large to expose a considerable part of the dorsum of the foot . the part of the port ( opening ) that is not needed will be closed by velcro straps . at least two such straps will be provided , the cephalad ( proxial ) strap will be carried over the intravenous access , and the caudad ( distal ) strap will be carried under the intravenous access tubing . the margin of the port will be reinforced to aid the straps in guaranteeing full compressive force over the foot in the area of the port . this will provide compression of the superficial veins despite the opening in the device . both the short and long embodiments will have an opening on the medial side to allow for putting on and removing the device . the opening will be closed with a zipper or velcro strip . the outer layer of both embodiments will be composed of firm , flexible but relatively non elastic woven fabric . this outer material is lined with an inner bladder which can be inflated to the desired pressure , suggested as 40 mm / hg . materials that are known to the art will be used for construction of both long and short embodiments of the device . two versions are described , one with a fixed pressure of 40 mm / hg and one with variable pressure . in both versions pressure will be attained by inflation of her inner bladder with a hand compressible elastic bulb with a single one way valve for inflation . a separate valve will be provided for deflation . in the fixed pressure version , an escape valve set at 40 mm / hg will be provided . this pressure has been shown to be sufficient to compress superficial veins . the variable pressure model will be provided with a pressure gauge . hereafter the bulb with or without the gauge will be referred to as the pneumatic compression regulator . the pneumatic compression regulator is shown in fig3 . this is a modification of u . s . pat . no . 5 , 108 , 456 ( apr . 28 , 1992 ). a commercially advantageous ( cost - saving ) feature , which renders our invention novel is a mechanism whereby the entire pneumatic compression regulator device may be detached from the compressive device at a point external to a one - way valve . this allows proper , safe consistent inflation without the need for the patient to lie with the valve fixed to the stocking . this will provide comfort to the bedridden patient and will allow the patient to change lying position readily without injury caused by the presence of the attached apparatus . in addition , this would reduce the cost since this part of the device could be used with more than one patient . this system of obtaining and maintaining pneumatic pressure will be applicable to other devices for application to the leg or arm . it will be desirable to interrupt the intravenous infusion of heparin for short periods as the patients become ambulatory . for this reason the inflatable bladder will not extend under the sole of the foot so as to avoid interference with walking . in one embodiment the inflatable bladder will stop short of the dorsum of the foot while in another it will extend to the end of the device in which case access to the dorsum of the foot will be provided by a port in the bladder . these devices will have some characteristics in common with the air inflatable compression devices . they will be made in a short ( above the ankle , i . e ., supramalleolar level ) and a long ( oust below the knee ) version to meet the needs of different clinical situations . the long version will be made with two different systems of closure : a set of velcro straps or a continuous velcro strip . the design of all versions ( embodiments ) is shown in fig4 and 5 . the inner lining of the stocking version is 1 . 5 to 2 . 0 cm circumferentially . this lining allows for consistent compression of the superficial veins over both the eminences and recessions of the surface topography of the foot , transmitting the 30 - 50 mm mercury pressure within an acceptable range of pressure from the distal transmetarsal level to the supramalleolar level . the outer encasing material is a flexible but relatively inelastic woven fabric within which the foam can be compressed to transmit the required pressure . the pressure compressing the inner foam lining is transmitted from the adjustable straps . there are four straps , measuring 1 . 5 cm × 5 cm . the elastic potion of the straps has a known elasticity , which is predicated by the elastic coefficient , the thickness and the width wherein the latter two parameters , a known determinable value by virtue of laboratory testing and manufacture . the proximal two ( supramalleolar ) straps are affixed to the medial aspect of the medial margin of the compressive device whereas both medial and lateral margins of the dorsal pedal aspect of the device are variably positionable ( removable at each margin ) by virtue of its velcro surfaces at both ends of the straps . the proximal two straps have velcro only at the medial aspect of the straps and are permanently affixed at the lateral ends . this ultimate flexibilityof the two distal straps insures ultimate flexibility in conforming to the position of the heparin lock which is predicated by the variations seen in each individual case . this establishes a dynamically variable and repositionable access port window . the compression devices as referred to herein describe both the embodiments of the compressive stocking and inflatable boot in regards to the positionability or lack thereof of both boot and stocking embodiments . we know of no existing prior art which offers the advantages associated with both user convenience and inexpensive construction in combination with an enforceable variably adjustable pressure application which is a known advantage of the various pneumatically inflatable boots . such advantages have ramifications to patient comfort where excess pressure need not occur as well as possible long - term clinical applications other than deep venous thrombosis prevents , where accurate pressure control is advantageous . by the same mechanism , it should be noted that distinct advantage can be seen with the use of our compressive stocking in lieu of torniquetion for venography , thereby insuring patient comfort by more consistently substantially reduced compressive force in lieu of a high pressure localized constrictive force . in addition this device eliminated a specific complication of venography , post contrast injection superficial venous pedal phlebitis . superficial phlebitis by current technique is induced by injecting contrast into the distended superficial venous plexus of the dorsum of the foot distal to the constricting proximal tourniquet . this creates stasis of the irritating contrast substance and causes endothelial initiative reaction and superficial phlebitis , which may result in a chronic smoldering inflammatory response and possible extension into deep venous thrombosis . our invention prevents this complication by compressive occlusion of the superficial veins and thereby eliminates stasis of contrast in the venous system , which would otherwise result from truncated occlusion of the superficial venous tourniquet occlusion . all embodiments will be made in small , medium and large to accommodate the large range of sizes of patients . both embodiments will be constructed with an outer and an inner layer , described below . both the short and long embodiments will have a port to provide access to the dorsum of the foot . because the size of the foot and the pattern of superficial veins will vary among patients , the port will be sufficiently large to expose a considerable part of the dorsum of the foot . the part of the port ( opening ) that is not needed will be closed by velcro straps . at least two such straps will be provided , the cephalad ( proximal ) strap will be carried over the intravenous access , and the caudad ( distal ) strap will be carried under the intravenous access tubing . the margin of the port will be reinforced to aid the straps in guaranteeing full compressive force over the foot in the area of the port . this will provide compression of the superficial veins despite the opening in the device . the outer layer ( shell ) of both embodiments will be composed of firm , flexible but relatively inelastic woven fabric . the inner layer ( lining ) will be composed of a layer of soft foam approximately 1 . 5 - 2 . 0 cm thick . this lining will allow for compression of the superficial veins over both the eminences and recessions of the surface of the foot and calf , uniformly transmitting the selected range of pressure ( 30 - 50 mm / hg ). the shell will be constructed of two sections . one section will extend from the knee or above the ankle to just below malleolar level . the othe will extend the length of the foot and will cover part of the dorsum , the sides and the sole . the two sections will be attached across the back and the sides to the malleolus . thereafter they will be separate . the top section will be attached so that one side is longer than the other in order to provide an overlap . this is necessary in order to adjust the device to the leg of the patient . pressure and closure will be obtained by adjusting the elastic closure devices . a novel means of providing both closure and adjusting pressure will be provided ( fig4 ). this is the incorporated to allow the clinician or nurse to use constant pressure or to vary the pressure gradient to promote venous return . in the short version four straps will be used . two straps will be used for obtaining closure and pressure of the part of the device above the malleolus . the opening ( port ) in the foot section of the shell will be closed by two straps that have velcro on both ends . this provides a means by which the pressure can be adjusted by adjusting the position of the straps . the straps will be triangular in shape with the base of the triangle attached to the device . in the long version , the device will extend to the level of the knee and will be fitted with a minimum of three additional straps . in another embodiment of the long version of the device a continuous closure will run the length of the shell on the medial side . again the elastic element will be attached to the shell of the device and the strip ( velcro or other material ) will be attached to the elastic element . the elastic plus velcro strip will be used for closure and for obtaining pressure . this variation insures consistent pressure at all levels of the device and implies an improvement over the multiple strap variation by eliminating the possibility of inconsistencies in pressure between the straps . the long version of both the strap and strip embodiments provides the options of having uniform or graded pressure over the calf with the strap embodiment the pressure at each strap ( level ) can be adjusted . with the strip embodiment , graded pressure can be obtained by tapering the overlap of the strip . current literature indicates that graded lower leg compression may augment the effectiveness of low dose heparin and suggests that the same will be true for other antithrombotic drugs . despite some of the known negative effects of using tourniquet and particularly of these above mentioned disadvantages with use in venography two of the significant advantages is simplicity ( in use ) and cost . as a result we further wish to describe a simple tourniquet which can be used to the greater safety and comfort to the patient by allowing the clinician to spot check the applied pressure during or after application . the present inventive concept is based upon a similar principle as that of the elastically gauged strap feature of the stocking embodiment herein described . the tourniquet described herein involves essentially the use of a clamped - on ( or otherwise attached ) windowed scale gauge which is geometrically calibrated and thus achieves a substantially similar functional objective and mechanism to that of the pressure gauging scale of the stocking embodiment described previously in this description ( see schematic ) in as much as the transparent window contains the scale which is from the viewers perspective superimposed over a reference marker by which the measured pressure is read . in other words , the numeric scale which is physically associated with the transparent window is read by the relative position of the reference marker in relation to relatively extensible overlying numeric scale which changes ( i . e ., increases ) with the degree of tension to which the tourniquet is physically stretch when applied to the patient . this geometrically calibrated scale printed upon said segment ideally ranges from 0 - 60 mmhg . almost all clinical applications which use this general type of tourniquet require an applied pressure within this range in order to retain clinical efficacy . in the manner thus described a phlebotomist may , while tightening in the process of tying the device quickly spot check the estimated approved pressure before committing application of the pressure as estimated . such a clinical procedural enhancement would likely be a potentially very useful adaptation to the long standing and currently held procedure regimen for tourniquet application . in one possible alternative embodiment a similar , however quite comparable degree of accuracy could be similarly achieved to that of the primary embodiment whereby the tourniquet essentially utilizes consistently and continuously spaced markers associated with the substantial portion comprising the body of the tourniquet , ( e . g ., the medial 75 % portion of the body of the tourniquet while each segment occupying the lateral portions of the device ( e . g ., the lateral 12 % portions on either end ) are occupied by a numbered geometrically calibrated scale similar to that of the fixed position scale of the straps of the stocking embodiment . the essential difference from that of the original preferred embodiment occurs in the clinician &# 39 ; s method of implementation which involves after affixing the procedure of tying the tourniquet manually pulling into position one of the lateral segment gauging scales zero points flush to the position of any one of the taught medical markers ( the entire lateral segment on either end of which is the untaught portion i . e ., the free end ). once the tension level of the tourniquet is checked the nurse or clinician may readjust accordingly until the desired tension ( in mmhg ) is achieved . it should be noted that one fundamental distinction between the presently disclosed enhanced method and apparatus and all other and currently known prior art involves the fact that these currently recognized and established compressive devices are generally used extra operatively and in patients with existing predisposing risk factors . these devices are designed functionally to preventing pooling of venous blood to thus help reduce the incidence of the troublesome substantially less severe superficial venous phlebitic syndrome as well as to improve lymphatic return often thereby also improving heart function . one more directly pertinent piece of prior art involves one application of the sequentially inflatable hip boot to the patient &# 39 ; s &# 39 ; legs particularly during the post operative period which is intended to reduce the incidence of deep venous thrombus formation . this device is well known to be uncomfortable due to the proximally directed sequential constrictive compressions which must be powerful enough to mobilize deep venous pooled blood which lies beneath the major muscular structures of the lower extremity and cumbersome as well as somewhat commercially impractical for clinical situations in light of an only moderate success level with respect to the overall clinical scope of the problem at hand . to the best of our knowledge there is in the current state of the art no known procedure moreover apparatus for the implementation thereof for substantially preventively reducing or eliminating the occurence of deep vein thrombosis post operatively . unlike the elastic strap variation because there is an inherent elasticity throughout the body of the entire device not unlike the elastic strap variation , because there is an inherent degree of elasticity throughout the body of the entire device ( not just at one short segment as in the strap embodiment ) an overall substantial elastic displacement ( stretch ) of the device may represent substantially much smaller relative displacement over any given increment such as the distance between two of the markers which are measured against the geometrically calibrated pressure determination scale , thus the geometrical calibrated scale must , by necessity , occupy a much reduced linear distance by contrast to that of the elastic strap embodiment variation of the present invention disclosure which accordingly must be appropriately considered , for the sake of ease and convenience as well as prevention of errors . in a further convenience enhanced variation ( for the benefit of the clinician ) color - coded segments superimposed upon a geometric scale indicate critically significant ranges of pressure which may define an appropriate particular application . this feature may also overcome to a certain extent the problem of legibility with regards to the scales occupying a relatively short linear span . it should be noted that the above described color coding feature may also be advantageously applied to the elastic strap variation as well for similar reasons of benefit those above described . there are several distinct advantages for various applications of a readily calibratible tourniquet as described and as would be apparently obvious to a skilled healthcare provider or other form of skilled clinician . the pressure straps or strips with gauging scale innately possesses broad commercial value in that the use of this inexpensive and convenient user friendly device is designed to assure accurate physician - recommended pressures for the pleurality of therapeutic variations for which medical stockings are currently used . the invention can be directly applied to venography in any situation including postoperative and routine venograms . the same technique can be used for regional thrombolytic agents ( streptokinase , urokinase or other compounds ) low - dose regional perfusion . the most likely circumstance would be to treat early known deep venous thrombosis . this is the simplest and least expensive embodiment of the devices for compressing the superficial veins of the foot and calf . however , it does not provide means for measuring or adjusting the pressure applied to the foot and calf this device will be made by installing a port in an existing graded elastic stocking , so that the dorsum of the foot can be exposed . the construction and closure of the port is the same as that for air inflatable and elastic strap / strip closure devices ( described above ). iv . detailed description of administering antithrombotic drugs for preventing and treating dvt clinical experience with angiography has shown that material infused into a superficial vein on the dorsum of the foot can be directed into the deep veins of the legs if the material is infused distal to the application of sufficient pressure to collapse the superficial veins . this concentrates the infused compound in the deep veins up to 100 fold the concentration that would be obtained by systemic administration . concentrating the infused antithrombotic drug in the deep veins of the legs would be an obvious advantage in both preventing development of dvt and treating preexisting dvt . preventing development of dvt prevents the risks of the patient having a pulmonary embolus or developing the postphlebitic syndrome . preventing growth of a deep vein thrombus that developed prior to start of treatment reduces the risk of pulmonary embolism and the postphlebitic syndrome since the risk of both conditions increases with the size of the thrombus . for both prevention and treatment of dvt , by heparin or other antithrombotic drug , the agent is to be infused into a superficial vein on the dorsum of the foot distal to application of sufficient pressure to compress sthe superficial venous system . this will provide a high local concentration of antithrombotic drug for preventing or treating deep vein thrombosis . a higher dose of antithrombotic drug may be required for treatment than for prevention . concurrent with the infusion of antithrombotic drug , pressure is to be applied to foot and calf if desired . pressure will be applied by one of the devices described in this patent application . access to the veins in sthe dorsum of the foot will be provided by the port in the device . the patient will be fitted with the compression device and the pressure adjusted to that judged most appropriate by the attending physician . this will be elevated by about 15 degrees . the protocol for intravenous administration of antithrombotic solutions can be developed by methods known in the art . for example , an intravenous solution containing 10 , 000 international units of heparin in 500 cc of fluid may be prepared by methods known in the art . this intravenous solution is administered at a volume rate of between about 19 and 31 cc / hr to provide a dose of between about 900 - 15 , 000 u per 24 hours . in a preferred embodiment , the volume rate of this solution is about 20 cc / hr to provide a dose of about 9600 u heparin per 24 hours . an infusion pump may be used for accurate volume administration . the regional perfusion employed in the above described methods for preventing deep venous thrombosis , thereby reducing the risk of pulmonary embolism and postphlebitic syndrome may be utilized in one or both legs as clinically indicated . further variations and modifications of the aforementioned can , of course , be made without departing from the spirit and scope of the invention as disclosed herein , and those skilled in the art will recognize multiple utilizations of the present invention that are within the scope of this disclosure . two bags each containing an intravenous solution of 5 % dextrose in water and approximately 10 , 000 international units of heparin are prepared . a small bore ( 20 - 22 gauge ) polyethylene catheter is inserted into the vein plexus on the dorsum of each foot of the host . a local anesthetic , for example , ½ % xylocaine may be administered prior to inserting the catheter . the catheter is then secured and the intravenous solution administered at a volume rate of approximately 19 - 31 cc / hr , preferably about 20 cc / hr into each lower extremity via an infusion pump . infusion of heparin or other antithrombotic drug will be continued substantially continuously for as long as clinically indicated . for surgical patients , infusion may be initiated just prior to or after surgery and continued for at least 24 - 72 hours post - operatively . infusion may be continued beyond 72 hours if clinically indicated . while standard heparin was used in the above detailed description of administering antithrombotic agents , the same methods can be used for administering low molecular weight heparin and other antithrombotic drugs such as those mentioned in the background . it is , of course , relevant within the spirit of the presently disclosed system and method that though at the time of the writing of this disclosure heparin and low molecular weight heparin were by far the prevailing drugs of choice in the preventative treatment of dvt , it would be obvious to one skilled in the art that with appropriate clinical and physiological adaptation to the present protocol herein disclosed that potential future drug analogs in the heparin class of pharmacological agents ( as well as potentially other classes as well ) could be efficaciously and prudently used in such fashion , so as to exploit the same physiological advantages of the present pharmacological delivery regimen over that of the prior art which uses the present novel principle of regional perfusion to the target regions of the peripheral venous system responsible for dvt . in an alternative embodiment heparin may be administered by injection with a one and one half inch 23 gauge needle into the soleal muscle directly which would provide direct regional and evenly sustained controlled outflow ( as is a characteristic feature of the intramuscular injection approach ) of heparin into the soleal venous plexus which is the known venous drainage for the principle culprits of the origin of dvt . the preferred administration calls for 2000 to 2500 units every 12 hours bilaterally by nurse or clinician . duration of administration is substantially identical to that of intravenous pedal administration . no monitoring of ptt or pt is necessary because of the low dose regionality without a substantial effect on overall levels systemically . it should be noted that in this embodiment there is no apparent need for the herein described pedal compression boot . possible consideration may be given in light of the current research literature for additionally using the graded compression stocking for the prevention of venous stasis . disadvantages of this approach include at least training of personnel for administering procedure and potential for muscle hematoma which should be self - limiting with termination of treatment or reversion to one of the alternate approaches herein described . in the case of prolonged treatment regimens , possible ensuing inflammation and resulting hematoma may be a primary concern . for this reason at the discretion of the clinician , varied directional approaches of the heparin injection may be utilized . finally in order to prevent ensuing leakage of the heparin following each injection resulting from retrograde flow through incompetent perforating veins proximal to the site of injection , external compression is recommended at the clinician &# 39 ; s discretion for patients suspect for predisposition to this potential problem . an alternative application of the above treatment regimen is the treatment of established diagnosed deep venous thrombosis . unlike that of the preventative approach 5000 - 8000 units every 12 hours are administered in the higher dose ranges monitoring ptt at certain intervals may be done at the clinician &# 39 ; s discretion ( which is also applicable for all other herein described variations of administration for controlling the treatment dosage ). the duration for administering the treatment regimen may be prolonged depending on the clinical needs and efficacy with regards to the clinical developments thereof . in yet another alternative embodiment heparin is administered into a suitable site of the soft tissues of the distal foot ( distal to the pedal compressive boot ) which is in this application used so as to guarantee delivery of heparin into the deep venous ( rather than superficial venous or superficial lymphatic ) system . because a venous access port is unnecessary in this application the enforced window as part of the pedal compressive boot or stocking described herein may be deleted from the device . as with that of the other embodiments described the recommended dosage is 2000 - 2500 units of heparin at 12 hour intervals bilaterally . it should be noted that in any one of these embodiments both dosage and frequency may be varied within certain limits according to clinical judgment . the preferred sites of soft tissue injection into the foot are the web spaces which can be advantageously alternated to minimize repeated insult to the tissues resulting from frequent injections . injection is performed with a 1 or 2 cc syringe and a 25 gauge needle . the needle and the injection must be put into the middle of the web space and the track of the needle must be directed proximally between the neurovascular bundles so as to avoid the digital neurovascular bundles . as with the other presently described alternative approaches the use of the present approach is equally well suited for use as a treatment regimen for confirmed dvt as well as the recommended higher dosage ranges mentioned and if recommend by the clinician also in connection with ptt monitoring as well . for extensively prolonged treatment regimens dosage levels may be modified to minimize tissue trauma at the discretion of the clinician or use of alternating regimens wherein varied forms of heparin are used may be considered as well in combination with the aforementioned approach of alternating the web spaces . the cases comprising the largest demand for use of this treatment are patients with spinal cord injury , particularly paraplegics , and long - term convalescent patients . the extent that the dosage can be reduced and still provide effective deep venous thrombosis prophylaxis has not yet been established . however , in addition to reduction in dosage levels , an alternative approach to administering this group is the utilization of the entire plantar surface wherein altered varied sites may be readily used for each injection . ( full exposure of the plantar surface is achieved by pulling down the distal end of the stocking or removing the stocking upon each administration ). it should be noted that this approach would not be practical in an ambulatory patient due to the compounding tissue insult from walking . it is likely under this regimen that most patients should be able to adapt to this form of administration indefinitely especially in light of a somewhat reduced dosage program . it should also be noted that there is a substantial clinical need which is widely recognized with regards to the above group particularly in spinal injury patients in as much as due to the overwhelmingly high percentages of dvt cited in this group even low dose heparin treatment is far from being a satisfactory resolution for adequately reducing this group &# 39 ; s morbid statistics . it should also be noted that for this approach because there is no need for a dorsal pedal access port ( as required for the continuous venous perfusion approach as previously described ) the exclusive role of the herein described windowed pedal compression boot as the sole dependable acceptable compressive tunic for applying the necessary compressive force of 40 mmhg . to substantially the entire foot does not apply in this regard in as much as a modified traditional compressive stocking with the distal tip removed which allows for full open exposure of the pedal digits and their corresponding intervening web spaces would be a reasonable alternative for the present approach provided that the substance of the distal portion of the foot is compressively covered so as to avoid swelling in the area of the exposed region . in light of this concern an alternative embodiment for a stocking involves utilization of either a traditional type compressive stocking or that of the pressure gauged elastic strap variation ( which as previously described above may be used as is , however , more preferably without the enforced dorsal access window ) for better enforced control of the ideal applied pressure . if , however , in accordance with the preferences of the hospital staff or clinician the device of choice is the traditional type compressive stocking , an enforced slit may be utilized in the stocking directly over ( i . e ., substantially over the level and somewhat narrower than the span of ) the underlying web spaces . ideally this slit is lined by a reinforced dual seam margin which minimizes the likelihood of a somewhat compromised ( reduced ) pressure application in the area of the slit or distally therefrom while worn . to further assure that this is the case , a single button may also be utilized which is positioned in the middle of the slit in order to provide both the continued compressive force in the toe region as well as convenient access to a nurse or clinician to the web spaces at the times of administration . immediately prior to injection into the web space of choice the attending nurse may after detaching the button stretch the distal tip of the stocking until the underlying digits thereof protrude so as to provide adequate accessibility to the intervening web space . in an alternative embodiment ( an additional modification ) of the traditional compressive stocking the stocking is designed such that there is no enclosed or tapered distal end . instead the distal portion is designed as such an open tubular configuration which extends somewhat beyond the level of the digits so as to allow in this variation both patient comfort with even compressive force over the entire foot as well as ease of access to the web spaces or plantar surface by the nurse or clinician just prior to administering the heparin injection by inverting and peeling back the end of the stocking ( extended ) sleeve so as to expose the web spaces or ( if desired ) the entire remaining portion of the foot without the obvious inconvenience to the patient and attending nurse of having to fully remove then replace the stocking before and after injection respectively . in all of the above described alternative approaches to delivering heparin into the deep venous system for prevention as well as treatment it should be noted that because of the recent study trials indicating the inherent multifold benefits low molecular weight heparin ( lmwh ) to be used in lieu of standard heparin for all similar applications that lmwh may be used alternatively wherever standard heparin is indicated not withstanding the fact as is known in the art that an enforced ratio of dosage for standard heparin may be used to calculate the corresponding adjusted dosage whenever lmwh is indicated by the clinician for use as a substitute for that of the standard heparin regimen ( this adjustment ratio is derived on the basis of several considerations including those of faster absorption rate , lower clearance time by the lever and greater potency by weight ) differences in clearance time from the body . the present concept pertains to a novel non - invasive method of heparin administration using an externally applied patch which may be directly analogous to other transdermally applied patches such as those used for nitroglycerin , scopolamine and nicotine application . the accompanying references describe the dosage parameters and basic construction of the device which includes a backing layer , a drug reservoir , a rate controlling membrane , contact adhesive and protective peel strip . it is believed that the low molecular weight variety heparinoid falls within the limits of the molecular weight threshold for transport across a cell membrane . though the molecular size is probably larger than similarly applied drugs , and may result in slower transdermal delivery , this regional perfusion approach which is used should more than compensate for this factor . in the preferred clinical application for patients at high risk for deep venous thrombosis , the transdermal patch is applied to the skin of the dorsal aspect of the pedal skin , prior to application of the compressive stocking ( which as previously described insures the substantial redistributing of drug laden blood to flow to the deep venous tributaries of the lower extremity ). alternatively , at the clinician &# 39 ; s discretion the heparin patch may be used in the sequence of a compressive stocking . therefore , because an adequate quantity of pedal blood makes its way to the deep venous system the heparin patch may , in certain situations , become a substitute to that of superficial graded compression especially in clinical situations involving long term sedation or a previous history of phlebitis . use of topically applied heparin to the dorsum of the foot can be considered without the concomitant use of the compressive boot or graded compression in situations where the use of the boot is precluded by leg wound ulceration , neuropathy or the patient &# 39 ; s refusal or discomfort . clinical applications include surgical and post surgical patients as well as long - term convalescent and cancer patients , convalescent stroke and accident related hemi - or quadriplegia . the clinical application is in the domain of deep venous thrombosis prevention . the efficacious advantages of the invention are ease and comfort of application , low cost and avoidance of immobility , which is a problem with heparin lock infusion , and length of active drug absorption . the clinical regimen calls for periodic application of heparin patch . low molecular weight heparin will require more frequent replacement of the patch due to higher absorption rates , while the higher molecule weight will provide slower released dosage and may be sustained for a longer duration . as with other transdermal drugs , the vehicle for administration may be different , for example , the use of drug laden pastes which may be applied under a gauze bandage , for direct dermal application in the form of an ointment or the drug in liquid form which may be used to saturate an absorbent medium or gauze covering . also as previously described , alternative anti - thrombogenic drugs ( non - heparinoid ) currently under investigation may show promise for the transdermal approach by virtue of their lower molecular weight properties ( thus facilitating absorption through the skin ). regarding the alternative variation of the drug in the form of a topical ointment , the heparin would be incorporated with a hydrophobic base , which would be topically administered in frequent and profuse quantities . such topical application in a partially compressive fashion may provide the further benefits of optimizing dermal contact even as the drug becomes absorbed and its relative concentration decreases as well as increased relative pressure differential between the absorbent medium and the skin which may further facilitate transdermal drug transport . finally , an alternative method would involve impregnation of heparin within a dissolvable hardened substrate which potentially may be well suited for subdermal administration primarily for longer term clinical situations so as to provide a guaranteed delivery of the drug . in addition because such techniques as those above suggested , reportedly only enables a limited degree of permeability of such otherwise sub - optimal permeability , larger molecule weight moieties such as enoxaparin , the use of such a transdermal device covering as large a region of the foot and / or ankle as is practically feasible may be duly indicated . it should be noted , that as this present description indicates , application to the skin of the distal lower extremity is ideal considering the relatively high molecular weight of the heparin moiety and consequent relative low absorption rate which may be compensated for by the concentrative effect of regional perfusion . alternatively , however , it may be determined through clinical studies that the various above - described procedures may show clinical benefit if applied to the external surface of the abdomen ( as a direct replacement for currently administered subcutaneous heparin ). the level of clinical benefit may be improved through the use of the lowest molecular weight anti - thrombogenic drugs currently available or currently under investigation . in any event , given a fixed absorption rate , transdermal delivery rate may be increased as well through use of patches covering a larger surface area of the patient &# 39 ; s skin . it can be appreciated that alternative transdermal drug delivery techniques such as those above suggested are ( as indicated in the case of the primary disclosed embodiment ) in no way intended to be limited to use within the context of delivery of heparin or heparin analogs exclusively that is if and when use of such alternative drug classes become discovered and clinically accepted for use within the present application . when considered in the context of the heretofore other proposed alternative embodiment ( above ) involving the use of ultrasonic transdermal delivery , it will become apparently obvious to the skilled reader of this section that each of the various alternative embodiments above suggested ( and potentially others ) could be further readily adapted for clinical use if administered in combination with these ultrasonic transdermal delivery techniques . because they would aptly provide a facilitatory role in drug delivery , it would be appropriate for example , while providing treatment for a specific clinical objective and situation at a specific level of aggressiveness and quantity of target drug delivered to modify the quantity , concentration and / or duration ( if periodic ) of topically delivered drug compensate appropriately for the increased absorptive rate achieved by virtue of the incorporation of ultrasonic transdermal facilitation into the present indicated protocol . and / or a given transdermal delivery protocol may become adapted as a viable alternative treatment approach for clinical situations which indicate a more aggressive drug delivery approach and as a consequence such an adaptation of the technique to the new clinical situation may be perhaps achievable by virtue of integrating such proposed ultrasonic drug delivery techniques into the otherwise less aggressive transdermally delivered treatment protocol such as those alternative embodiments herein suggested . because the energy levels of the ultrasonic transducer device is of a relatively low intensity level , the use of ultrasound techniques may be an alternative embodiment facilitating absorption . at the time this application is written such techniques are in clinical investigational stages and possibly in limited clinical use . the use of this type of device in form of a patch - like device for transdermal delivery of compounds are currently on display at the tech museum innovation in san jose , calif . the suggested methods exemplified herein by the presently proposed alternative embodiments have been provided herein in order to exemplify and elucidate the substantial range of alternative clinical treatment approaches each of which may be potentially viable and perhaps most efficacious for each of the comparably varied range of differing clinical situations ( wherein the myriad array of differing clinical situations must be considered whose needs vary in accordance with differing treatment variations in the preventative approaches to dvt ). for example , these may span the spectrum from more aggressive treatment protocols as in more acutely immobile patients to those less aggressive treatment approaches for more moderate degree of need for clinical treatment intervention . thus the presently suggested alternative embodiments are herein provided accordingly and in no way are intended to limit the broad scope of the claimed inventive concepts or the potential incorporation of as yet unforeseen or future clinical situations , pharmacological agents and / or their associated indicated treatment protocols . this may be particularly true if / when newly discovered techniques become clinically adopted and accepted for transdermal drug delivery . for example , in addition to ( or with appropriate modifications , in conjunction with ) ultrasonic transdermal delivery , non - syringe based pressure injection drug delivery methods for delivery of pharmacological agents are yet still another technique which has been discovered relatively recently and discussed and tested to a limited degree in clinical situations and thus could form the basis for an alternative delivery device to the above syringe - based delivery approach as embodied herein . likewise , in the case of alternative ( or future alternative ) drugs and classes thereof as aforementioned , for delivery via the primary embodiment or utilizing any of the variety of alternative delivery modalities such as those above described , it is worthy to note that such various other classes of drugs could potentially become discovered and incorporated in wide scale clinical use within a relatively short time frame . in particular , recent advances in proteinomics for use in drug discovery are creating a whole new generation of super drugs and drugs whose , behavioral properties ( and conceivably even , size ) could be customized to a particular clinical situation , or even individual patient . it is also possible that more highly specialized drugs may suggest the possibility of new opportunities by which they could also be delivered in combinatorial fashion if the combined effects are desirable and safe . for example , one could easily consider the possibility in this newly emerging environment of designer drugs for which different properties are desirable and efficacious for particular types of clinical situations requiring dvt prevention . ( this also does not preclude the possibility of providing these associated desired properties through the administration of the relevant associated drugs in combination with one another ) . some of these properties may include ( but are not limited to ): 2 . very small molecular weight ( e . g ., whereby the “ target receptor ” interacting portion of the agents &# 39 ; molecular moiety could be isolated and thus significantly reduce the molecular size of the molecule to within the range needed for a readily transdermally absorbable drug . 3 . vasoactive properties , as indicated above , such as can be exhibited with dihydroergotamine mesylate which possesses such properties and has been shown to provide further incremental advantages over that of a standard low molecular weight analog in deep venous thrombus prevention when administered in combinatorial fashion with low molecular weight heparin compared to the use of lmw heparin by itself . invariably higher concentration levels of drugs possessing such vasoactive properties which are achievable via the presently disclosed methods for regional perfusion to the lower extremity could further reduce the risk of dvt by further decreasing stasis of pooling deep venous blood . in this alternative embodiment , the preferred delivery protocol as herein suggested indicates an approximately similar relative percentage concentration of dihydroergotamine to lmw heparin as that relative concentration used in the above referenced experiment conducted by gwendolyn stewart ( or appropriately adjusted concentrations of any other vasocontrictive pharmacological analog of preference ). the present low molecular weight properties of dihydroergotamine provide one distinct advantage which is its absorptive properties when administered transdermally . 4 . anti - inflammatory properties — this characteristic of a drug would server potentially useful benefits : a . avoiding or minimizing the inflammatory response to the delivery site subdermally . b . reducing the inflammatory response to the drug at or near the endothelium of the venous wall which could activate leukocyte and / or platelet aggregation activity ( certain particular consideration to the negative effects of inflammatory response to certain drugs should be considered , for example , as may be relevant to the administration of vasoconstrictors ). 5 . properties which are selectively activated in response to certain discreet physiological or biochemical processes such as the aggregation of platelets , or leukocytes or the “ clotting cascade ” and its associated enzymatic activity or 6 . simply agent - related properties , which interrupt the biochemical process which enables platelet aggregation to occur . this novel approach to deep venous thrombosis prevention provides some definite inherent advantages over the traditional approach to anticoagulant therapy . 1 . avoid frequent monitoring of prothrombin and partial thromboplastin times , thus , 2 . traditional heparin can be administered at a much lower cost and , 7 . possibly reduce hospital length of stay for high risk patients , e . g ., following major extremity orthopedic surgery . 8 . reduced cost also related to ability to substitute heparin therapy for lovenox therapy with substantial drug savings . 1 hume m , sevitt s , thomas d p mechanisms of venous thromboembolism in hume m , sevitt s , thomas d p , eds . venous thrombosis and pulmonary embolism . cambridge , mass : harvard university press ; 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120 . 527 - 530 33 . prandoni p , lensing a w a , cogo a , cuppini s , villalta s , carta m , cattelan a m , polistena p , bernardi e , prins m h . the long - term clinical course of acute deep - vein thrombosis . ann intern med . in press . 34 . zilliacus h . on the specific treatment of thrombosis and pulmonary embolism with anticoagulants , with a particular reference to the post thrombotic sequelae . acta med scand . 1946 ; 170 . 1 - 221 . 35 . huisman m v , buller h r , ten cate j w , vreeken j . serial impedance plethysmography for suspected deep vein thrombosis in outpatients . the amsterdam general practitioner study . n engl j med . 1986 ; 314 . 823 - 828 . 36 . hull r , delmore t , carter c , hirsh j , genton e , gent m , turpie a g g , mcloughlin d . adjusted subcutaneous heparin vs warfarin sodium in the long - term treatment of venous thrombosis . n engl j med . 1982 ; 306 : 189 - 194 . 37 . hull r , hirsh j , jay r m , carter c , england c , gent m , turpie a g g , mcloughlin d , dodd p , thomas m , raskob g , ockelford p . different intensities of oral anticoagulant therapy in the treatment of proximal - vein thrombosis . n engl j med . 1982 ; 307 : 1676 - 1681 . 38 . hull r , delmore t , genton e , hirsh j , gent m , sackett d , mcloughlin d , armstrong p . warfarin sodium versus low - dose heparin in the long - term treatment of venous thrombosis . n engl j med . 1979 ; 301 : 855 - 858 . 39 . salzman e w , deykin d , shapiro r m , rosenberg r . management of heparin therapy : controlled prospective trial . n engl j med . 1975 ; 292 : 1046 - 1050 . 40 . glazier r l , crowell e b . randomized prospective trial of continuous vs intermittent heparin therapy . jama 1976 ; 236 : 1365 - 1367 . 41 . basu d , gallus a , hirsh j , cade j . a prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time . n engl j med . 1972 ; 287 : 324 - 327 . 42 . prandoni p , lensing a w a , buller h r , carta m , cogo a , vigo a m , casara d , ruol a , ten cate j w . comparison of subcutaneous low - molecular - weight heparin with intravenous standard heparin in proximal deep - vein thrombosis . lancet . 1992 ; 339 : 441 - 445 . 43 . brandjes d p m , heijboer h , de rijk m , jagt j , buller h r , ten cate j w , huisman m v . the effect of graded compression stockings on the development of the post - thrombotic syndrome in patients with proximal deep - vein thrombosis . thromb haemost . 1991 ; 65 ( suppl ): 1131 . abstract . 44 . prandoni p , lensing a w a , buller f r , cogo a , prins m h , cattelan a m , cuppini s , noventa f , ten cate j w . deep - vein thrombosis and the incidence of subsequent symptomatic cancer . n engl j med . 1992 ; 327 : 1128 - 1133 . 45 . hirsh j . the optimal duration of anticoagulant therapy for venous thrombosis . n engl j med . 1995 , 332 : 1710 - 1711 . 46 . levine m n , hirsh j , gent m , turpie a g g , weitz j , ginsberg j , geerts w , leclerc j , neemeh j , powers p , piovella f . optimal duration of oral anticoagulant therapy : a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis . thromb haemost . 1995 , 74 : 606 - 611 . 47 . optimum duration of anticoagulation for deep - vein thrombosis and pulmonary embolism . lancet . 1992 ; 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79 : 1 - 77 . 66 . anderson d r , o &# 39 ; brien b j , levine m n , roberts r , wells p s , hirsh j . efficacy and cost of low - molecular - weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty . ann intern med . 1993 ; 119 : 1105 - 1112 . 67 . hull r , delmore t j , hirsh j , gent m , armstrong p , lofthouse r , macmillan a , blackstone i , reed - davis r , detwiler r c . effectiveness of intermittent pulsatile elastic stockings for the prevention of calf and thigh vein thrombosis in patients undergoing elective knee surgery . thromb res . 1979 , 16 : 37 - 45 . 68 . wille - jorgensen p , thorup j , fischer a , hoist - christensen j , flamsholt r . heparin with and without graded compression stockings in the prevention of thromboembolic complications of major abdominal surgery : a randomized trial . br j surg . 1985 , 72 : 579 - 581 . 69 . wille - jorgensen p , christense b w , bjerg - nielsen a , stadeager c , kjaer l . prevention of thromboembolism following elective hip surgery the value of regional anesthesia and graded compression stockings . clin orthop 1989 , 247 : 163 - 167 . 70 . powers p j , gent m , jay r m , julian d h , turpie a g g , levine m , hirsh j . a randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip . arch intern med . 1989 ; 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