Bone marrow shielding apparatus and method of bone marrow-shielded cancer chemotherapy

Abstract

The invention provides a variety of bone marrow-shielding tourniquets and methods for using them to perform bone marrow-shielded chemotherapy with or without general and without the need to remove a patient's bone marrow for protection during the procedure. In the invention method, pressure is applied to at least one body part of the patient that contains myelopoietic bone marrow to temporarily occlude arterial flow to the bone marrow while blood circulation through the remainder of the body is maintained. Then an effective amount of at least one myelosuppresive chemotherapeutic agent is administered to the blood circulation in the remainder of the patient while the arterial flow through the at least one body part is occluded and so that the myelosuppresive effect of the agent is substantially dissipated within the maximum safe period for the occlusion of the arterial flow, or about three hours. The pressure is removed to restore blood circulation to the bone marrow when the effect has substantially dissipated and within the maximum safe period. By the invention method, a tumor located in the remainder of the body is treated by the at least one chemotherapeutic agent without destruction of a substantial portion of the bone marrow in the occluded body part. The bone marrow shielding tourniquets for use in the invention chemotherapeutic method are designed to substantially cover at least the shoulder or hip area of a human so as to occlude arterial flow therein and include inflatable bladders that apply the requisite pressure when the tourniquet is applied to the wearer. The shoulder tourniquet optionally is designed to occlude arterial flow into the proximal scapula as well as into the shoulder area. Bilateral tourniquets are also provided for simultaneous occlusion of bilateral shoulders and, optionally, bilateral scapulae.

What is claimed is:  
     
         1 . A method for bone marrow-shielded chemotherapeutic treatment of a patient in need thereof, said method comprising: 
 applying pressure to at least one body part of the patient that contains myelopoietic bone marrow to temporarily occlude arterial flow to the bone marrow while blood circulation through the remainder of the body is maintained,    administering to the blood circulation in the remainder of the body an effective amount of at least one myelosuppresive chemotherapeutic agent while the arterial flow through the at least one body part is occluded and so that the myelosuppresive effect of the agent is substantially dissipated within the maximum safe period for the occlusion of the arterial flow, and    removing the pressure to restore blood circulation to the bone marrow when the effect has substantially dissipated and within the maximum safe period,    wherein a tumor located in the remainder of the body is treated by the at least one chemotherapeutic agent without destruction of a substantial portion of the bone marrow in the at least one body part, and without general anesthesia.    
     
     
         2 . A method for bone marrow-shielded chemotherapeutic treatment of a patient in need thereof, said method comprising: 
 applying a bone marrow shielding tourniquet to at least one body part of the patient that contains myelopoietic bone marrow to temporarily occlude arterial flow to the bone marrow while blood circulation through the remainder of the body is maintained,    administering to the blood circulation in the remainder of the body an effective amount of at least one myelosuppresive chemotherapeutic agent and while the arterial flow through the at least one body part is occluded so that the myelosuppresive effect of the agent is substantially dissipated within the maximum safe period for the occlusion of the arterial flow, and    removing the bone marrow shielding tourniquet to restore blood circulation to the bone marrow when the effect has substantially dissipated and within the maximum safe period.    
     
     
         3 . The method according to    claim 2    wherein the chemotherapeutic agent has a known period of initial half-life and the tourniquet is removed about 1 minute to about 2 hours after passage of the known period of initial half life.  
     
     
         4 . The method according to    claim 2    wherein the method is practiced without general anesthesia and the maximum safe period is about three hours.  
     
     
         5 . The method according to    claim 3    wherein the known period of initial half-life is about 10 seconds to about 25 minutes and the removing of the tourniquet is about 15 minutes after passage of the known period of initial half life.  
     
     
         6 . The method according to    claim 2    wherein the tourniquet applies a pressure substantially greater than the systolic blood pressure of the patient.  
     
     
         7 . The method according to    claim 6    wherein the pressure is from about 5mmHg to about 300 mmHg above the systolic blood pressure.  
     
     
         8 . The method according to    claim 7    wherein the pressure is from about 50 mmHg to about 200 mmHg above the systolic blood pressure.  
     
     
         9 . The method according to    claim 2    wherein the pressure is substantially equalized over the body surface covered by the tourniquet.  
     
     
         10 . The method according to    claim 2    wherein the method is repeated at spaced intervals of from eight hours to two months.  
     
     
         11 . The method according to    claim 10    wherein the repeating is for up to 20 repeats.  
     
     
         12 . The method according to    claim 2    wherein the arterial flow is occluded for a period of from about 5 minutes to about 2 hours.  
     
     
         13 . The method according to    claim 2    wherein the body part is a shoulder and/or a hip and the method further comprises exsanguinating the arm proximal to the shoulder and/or leg proximal to the hip prior to application of the tourniquet.  
     
     
         14 . The method according to    claim 13    wherein the exsanguinating involves applying an Esmarch bandage or gravity drainage of the arm or leg.  
     
     
         15 . The method according to    claim 2    wherein the tourniquet is inflatable and the applying involves inflation of the tourniquet to apply the pressure around the at least one body part.  
     
     
         16 . The method according to    claim 2    wherein the at least one body part is a shoulder and the tourniquet occludes arterial flow into the proximal upper ⅓ of the humerus of the patient.  
     
     
         17 . The method according to    claim 15    wherein the at least one body part includes both shoulders and the tourniquet occludes arterial flow into the proximal upper ⅓ of the humeri of the patient.  
     
     
         18 . The method according to    claim 2    wherein the at least one body part includes a hip and the tourniquet occludes arterial flow into the proximal upper ⅓ of the femur of the patient.  
     
     
         19 . The method according to    claim 17    wherein the at least one body part includes both hips and the tourniquet occludes arterial flow into the respective proximal upper ⅓ of the femurs of the patient.  
     
     
         20 . The method according to    claim 2    wherein the at least one body part includes a scapula of the patient.  
     
     
         21 . The method according to    claim 2    wherein the at least one body part includes both scapulae of the patient.  
     
     
         22 . The method according to    claim 2    wherein the at least one body part is selected from the group consisting of an upper femur, an upper humerus, and a scapula of the patient, and combinations of two or more thereof.  
     
     
         23 . The method according to    claim 2    further comprising administering to the patient an effective amount of one or more active agents for relieving pain, anxiety, nausea or vomiting.  
     
     
         24 . The method according to    claim 23    wherein the one or more active agents are administered before the tourniquet is applied.  
     
     
         25 . The method according to    claim 2    wherein the chemotherapeutic agent is cytotoxic against the type of tumor being treated.  
     
     
         26 . The method according to    claim 25    wherein the chemotherapeutic agent is mechlorethamine and the effective amount is in the range from about 0.1 mg/kg to about 1.6 mg/kg of body weight of the patient.  
     
     
         27 . The method according to    claim 26    wherein the effective amount is in the range from about 0.2 mg/kg to about 0.6 mg/kg of body weight of the patient.  
     
     
         28 . The method according to    claim 26    wherein the tumor is associated with a cancer selected from the group consisting of Hodgkin's disease, lymphoma, sarcoma, and skin, lung, breast, brain, colon, rectal, uterine, stomach, liver, kidney, pancreas, prostate, testicular and ovarian cancer.  
     
     
         29 . The method according to    claim 2    wherein the method further comprises administering highly oxygenated autologous blood into the occluded body part while the tourniquet is applied.  
     
     
         30 . The method according to    claim 2    wherein the method further comprises chilling the occluded body part during at least a portion of the time during which the tourniquet is applied.  
     
     
         31 . The method according to    claim 2    wherein the body part includes both shoulders and wherein the method further comprises administering the chemotherapeutic agent via a central venous catheter.  
     
     
         32 . The method according to    claim 74    further comprising administering to the patient an effective amount of a cytokine selected from the group consisting of Granulocyte-colony stimulating factor, granulocyte-macrophage-colony stimulating factor, stem cell factor, erythropoietin, thrombopoietin, interleukin-11, and suitable combinations thereof.  
     
     
         33 . A bone marrow shielding tourniquet adapted to apply pressure around a shoulder or hip of a human, said tourniquet comprising 
 an inflatable bladder contoured for covering the shoulder or hip and having an inner face and an outer face,    a fluid-tight connector attached to the inflatable bladder for attaching the bladder to a source of fluid pressure, and    a substantially inelastic exterior layer substantially covering the outer face of the bladder so as to limit expansion of the bladder in the direction of the exterior layer when the bladder is inflated by fluid from the fluid source.    
     
     
         34 . The tourniquet according to    claim 33    wherein the exterior layer is semi-flexible or inflexible and has a three-dimensional shape selected to hold the bladder around the shoulder or hip area.  
     
     
         35 . The tourniquet according to    claim 34    further comprising a co-operative fastener attached to the tourniquet for releasably affixing the tourniquet around the hip or shoulder.  
     
     
         36 . The tourniquet according to    claim 34    further comprising a flexible interior layer lining the inner face of the bladder.  
     
     
         37 . The tourniquet according to    claim 36    wherein the exterior layer and interior layer co-operatively form an envelope for containing the bladder and wherein inflation of the bladder causes the bladder to extend the flexible interior layer, and wherein the fastener is attached to or contiguous with the envelope so formed so that engagement of the fastener affixes the tourniquet snugly around the hip or shoulder in contact with the interior layer.  
     
     
         38 . The tourniquet according to    claim 34    wherein the flexible bladder has two longer, arcuate sides, and two shorter, straight sides.  
     
     
         39 . The tourniquet according to    claim 38    wherein one arcuate side describes a larger arc than the other and the bladder has an overall shape described by the difference between the sectors of two circles having a common center and swept out by a common angle, but having radii of substantially different length.  
     
     
         40 . The tourniquet according to    claim 39    wherein the difference in the length is from about 2 inches to about 10 inches.  
     
     
         41 . The tourniquet according to    claim 38    wherein the arcuate sides are substantially equal in length and are arranged in mirror image to one another so that the tourniquet has an overall hour glass shape.  
     
     
         42 . The tourniquet according to    claim 34    wherein the bladder is pressurizable to at least about 300 mmHg and, when affixed around a shoulder or hip and inflated, occludes arterial flow to the myelopoietic bone marrow therein.  
     
     
         43 . The tourniquet according to    claim 34    further comprising at least one protuberance on the inner face of the bladder, which protuberance is sized and located to fill in an anatomical hollow in the shoulder or hip.  
     
     
         44 . The tourniquet according to    claim 37    further comprising at least one protuberance on the interior layer, which protuberance is sized and located to fill in an anatomical hollow in the shoulder or hip.  
     
     
         45 . The tourniquet according to    claim 43    wherein the protuberance is attached to the surface of the interior layer.  
     
     
         46 . The tourniquet according to    claim 34    wherein the tourniquet is adapted for affixation around the shoulder to occlude arterial flow into the proximal upper 1/3 of the proximal humerus.  
     
     
         47 . The tourniquet according to    claim 45    wherein the tourniquet is adapted for affixation to the shoulder of a human and the protuberance is adapted to fill in an arm pit.  
     
     
         48 . The tourniquet according to    claim 46    and the tourniquet further comprises a brace attached to the tourniquet, said brace being adapted to hold an arm attached to the shoulder at a fixed angle from the side of the torso to which the shoulder attaches when the tourniquet is affixed around the shoulder.  
     
     
         49 . The tourniquet according to    claim 48    wherein the brace is adapted to elevate the arm proximal to the shoulder at an angle of from about 45 degrees to about 180 degrees from the proximal side of the torso when the tourniquet is affixed around the shoulder.  
     
     
         50 . The tourniquet according to    claim 48    wherein the brace extends along the side of the torso proximal the shoulder and wherein the tourniquet further comprises a brace fastener attached to the portion of the brace that extends along the proximal side of the torso for fastening around the torso when the tourniquet is affixed around the shoulder.  
     
     
         51 . The tourniquet according to    claim 48    wherein the tourniquet further comprises a positioning fastener, which positioning fastener is attached to the tourniquet for fastening around the torso to prevent migration of the tourniquet from the affixed position around the shoulder.  
     
     
         52 . The tourniquet according to    claim 34    wherein the tourniquet is adapted for affixation around the hip to occlude arterial flow into the proximal upper ⅓ of the proximal femur.  
     
     
         53 . The tourniquet according to    claim 52    further comprising a hip positioning fastener attached to the tourniquet to embrace the pelvis of a human to prevent migration of the tourniquet from around the hip.  
     
     
         54 . The tourniquet according to    claim 53    wherein the hip positioning fastener comprises a fabric hook and loop fastener system.  
     
     
         55 . The tourniquet according to    claim 52    wherein the tourniquet further comprises a brace attached to the tourniquet, said brace being adapted to hold a thigh proximal to the hip at a fixed angle from the proximal side of the torso when the tourniquet is affixed around the hip.  
     
     
         56 . The tourniquet according to    claim 55    wherein the brace is adapted to hold the thigh at an angle of from about 45 degrees to about 155 degrees from the proximal side of the torso when the tourniquet is affixed around the hip.  
     
     
         57 . The tourniquet according to    claim 34    wherein the exterior layer is made of a material selected from the group consisting of artificial polymer, leather, plaster of Paris, metal, natural woven fiber, and combinations thereof.  
     
     
         58 . The tourniquet according to    claim 34    wherein the tourniquet is designed for affixation to an extremity and the tourniquet further comprises an attached brace for holding the extremity at a fixed angle from the torso.  
     
     
         59 . A bilateral bone marrow shielding tourniquet, said bilateral tourniquet having an anterior and a posterior side and comprising two tourniquets according to    claim 34    in mirror image arrangement and further comprising a releasable anterior positioning fastener for releasably joining the anterior portions of the two tourniquets.  
     
     
         60 . The bilateral bone marrow shielding tourniquet according to    claim 59    wherein the anterior positioning fastener comprises two cooperative parts, each attached to the anterior portion of one of the tourniquets.  
     
     
         61 . The bilateral bone marrow shielding tourniquet according to    claim 59    further comprising a releasable anterior positioning fastener for releasably joining the posterior portions of the two tourniquets.  
     
     
         62 . The bilateral bone marrow shielding tourniquet according to    claim 59    wherein the anterior positioning fastener comprises two cooperative parts, each attached to the anterior portion of one of the tourniquets.  
     
     
         63 . The bilateral bone marrow shielding tourniquet according to    claim 59    wherein the bilateral tourniquet is adapted for simultaneously occluding arterial flow into the proximal upper ⅓ of both upper femurs of a human.  
     
     
         64 . The bilateral bone marrow shielding tourniquet according to    claim 59    wherein the bilateral tourniquet is adapted for simultaneously occluding arterial flow into the proximal upper ⅓ of both humeri of a human.  
     
     
         65 . A bilateral hard shell bone marrow shielding tourniquet adapted for wearing by a human, said tourniquet comprising: 
 a semi-flexible or inflexible and inelastic carapace in one or more pieces, wherein the carapace has a three-dimensional shape adapted to substantially cover at least the bilateral scapular areas and/or shoulder areas of a wearer while allowing the head, arms, and torso to protrude from the carapace.    
     
     
         66 . The tourniquet according to    claim 65    further comprising: 
 bilateral inflatable bladders attached along the interior surface of the carapace that, when inflated, apply pressure over at least the bilateral scapular areas and/or shoulder areas of the wearer, and  
 a fluid-tight connector on each inflatable bladder for inflating the bladder,  
 wherein inflation of one or both bladders causes the tourniquet to exert sufficient pressure upon the respective covered areas of the wearer to occlude arterial flow into at least the covered areas.  
 
     
     
         67 . The tourniquet according to    claim 66    further comprising at least one adjustable fastener attached to the carapace for cinching the carapace about the torso of the wearer.  
     
     
         68 . The tourniquet according to    claim 67    wherein the carapace is in two pieces for arranging in mirror image fashion about the wearer to create the three-dimensional shape.  
     
     
         69 . The tourniquet according to    claim 67    wherein the two pieces of the carapace each has an arm hole for receiving an arm of the wearer and an anterior and a posterior side, and wherein the arranging involves placing the wearer's arms through the arm holes and moving the two pieces of the carapace about the shoulders and scapulae of the wearer to co-operatively substantially cover the bilateral scapulae and shoulders of the wearer, and cinching the carapace about the torso of the wearer.  
     
     
         70 . The tourniquet according to    claim 69    wherein the tourniquet comprises at least two fasteners, one for joining the anterior sides of the two pieces across the anterior torso of the wearer and one for joining the two posterior sides of the two pieces across the posterior torso of the wearer.  
     
     
         71 . The tourniquet according to    claim 69    wherein the bilateral bladders, each substantially cover the respective shoulder area and proximal scapula of the wearer.  
     
     
         72 . The tourniquet according to    claim 71    wherein inflation of the bilateral bladders applies sufficient pressure against the body of the wearer to bilaterally occlude arterial flow into the upper ⅓ of the proximal humerus and scapula.  
     
     
         73 . The tourniquet according to    claim 67    wherein the carapace is semi-flexible and in one piece with a neck/chest opening adapted for receiving the wearer's head and at least one slit that opens to enable the tourniquet to be placed about the wearer and closes about the wearer to assume the three dimensional shape.  
     
     
         74 . The tourniquet according to    claim 66    wherein the carapace and the inflatable bladders cover the bilateral scapular areas of the wearer, but not the bilateral shoulder areas.  
     
     
         75 . A hard shell bone marrow shielding tourniquet adapted for applying pressure to a scapular area of a human wearer, said tourniquet comprising: 
 a substantially inflexible and inelastic carapace in one pieces having a three-dimensional shape adapted to substantially cover at least the scapular area of a wearer while allowing the head, arms, and torso to protrude from the carapace,    an inflatable scapular bladder attached along the interior surface of the carapace that, when inflated, applies pressure over the bilateral scapular area of the wearer,    a fluid-tight connector on the inflatable bladder for inflating the bladder, and    at least one adjustable fastener attached to the carapace for cinching the carapace about the torso of the wearer,    wherein inflation of the bladder causes the tourniquet to exert sufficient pressure upon the scapular area of the wearer to occlude arterial flow thereinto.    
     
     
         76 . An inflatable bladder comprising an inflatable bladder piece having a shape adapted to substantially cover the hip area or at least the shoulder area of a human and a fluid tight connector on the bladder.  
     
     
         77 . The bladder according to    claim 76    wherein the bladder piece has a shape adapted to substantially cover the shoulder area and proximal scapula of the human.  
     
     
         78 . A method for fabricating an individualized bone marrow shielding tourniquet, said method comprising: 
 (a) wrapping a hip or shoulder to be compressed for occlusion of arterial blood flow therein with an inflatable bladder having a fluid-tight connector,    (b) wrapping the inflatable bladder with a softened orthopedic cast material so as to leave free the connector, and    (c) molding the cast material and the one or more inflatable bladders around the hip or shoulder under conditions suitable for causing the orthopedic cast material to harden.    
     
     
         79 . The method according to    claim 78    wherein the method further comprises wrapping the shoulder or hip to be compressed with a cushioning material prior to wrapping the one or more inflatable bladders around the hip or shoulder.  
     
     
         80 . The method according to    claim 79    wherein the cushioning material is moisture absorbent.  
     
     
         81 . The method according to    claim 79    wherein the cushioning material is stockinet, cast padding, or cotton sheet, or a combination thereof.  
     
     
         82 . The method according to    claim 80    wherein the orthopedic cast material is a knitted substrate impregnated with polyurethane resin or plaster of Paris.  
     
     
         83 . A method for protecting myelopoietic marrow cells from the effects of chemotherapeutic agents without the need for physical removal of bone marrow cells from the body of a patient in need thereof, said method comprising: 
 applying pressure to at least one body part of the patient that contains myelopoietic bone marrow to temporarily occlude arterial flow to the bone marrow while blood circulation through the remainder of the body is maintained,    administering to the blood circulation in the remainder of the body an effective amount of at least one myelosuppresive chemotherapeutic agent while the arterial flow through the at least one body part is occluded and so that the myelosuppresive effect of the agent is substantially dissipated within about three hours of commencement of the application of the pressure, and    removing the pressure to restore blood circulation to the bone marrow when the effect has substantially dissipated and within the three hours.    
     
     
         84 . The method according to    claim 83    further comprising administering to the patient an effective amount of a cytokine selected from the group consisting of Granulocyte-colony stimulating factor, granulocyte-macrophage-colony stimulating factor, stem cell factor, erythropoietin, thrombopoietin, interleukin-11, and suitable combinations thereof.  
     
     
         85 . The method according to    claim 84    further comprising administering the chemotherapeutic agent to the via a central venous catheter.  
     
     
         86 . The method according to    claim 85    wherein the catheter is placed into a vein selected from the group consisting of internal jugular, external jugular, and subclavian veins.