Abstract:
A central-vein cathether is locked by anticoagulant and bactericidal solutions separated by an air bubble. The anticoagulant is injected first, then the air bubble, and then the bactericidal solution, so that the anticoagulant is located close to the catheter tip in contact with the blood and the bacterial solution is located close to the catheter hub, where bacteria contamination is common. The air bubble prevents mixing of the solutions. A multi-chamber syringe facilitates sequential injection of the anticoagulant, air and bactericidal agent with only one connection, decreasing chances of contamination. The syringe includes internal and external coaxial barrels separated by seals, the external barrel having a discharge opening located off center in the barrel bottom, and the internal barrel having two or three chambers, each with an outlet opening. The internal barrel is rotatable relative to the external barrel to consecutively align the outlet openings with the discharge opening, allowing sequential injection of the contents. The syringe may also be used for aspiration of the locking fluid from the catheter with only one connection.

Description:
BACKGROUND 
     This invention relates to implanted intravenous catheters and, in particular, to techniques for locking such catheters between uses and for prevention of infection. 
     Intravenous catheters are increasingly used as blood accesses for hemodialysis, plasmapheresis, and for infusion of drugs and nutrients. There are two major complications of intravenous catheters: thrombosis and infection. Both are at least partly related to the method of locking the catheter lumen in periods between uses. 
     Catheter Locking 
     Soft, cuffed, single or dual-lumen, central-vein catheters are commonly used as permanent blood accesses. Between uses they are locked by being filled with a fluid to isolate the patient&#39;s vascular system from the environment. To prevent clotting, the entire lumen or lumens of such catheters, from hub to tip, are commonly filled with an anticoagulant in the period between uses. This locking solution is aspirated prior to the next use with a syringe and discarded. If the solution cannot be aspirated, because the catheter lumen is clotted, the solution is pushed into the venous system. Such injection of the locking solution may cause excessive anticoagulation or other side effects. 
     Heparin is the most commonly used anticoagulant to lock catheters between uses. Each lumen is locked with 5,000 to 10,000 units of heparin after dialysis. This solution must be withdrawn from the catheter before the next use, since this much heparin may result in bleeding if infused into the patient. Heparin exerts its anticoagulant activity mainly through activation of Anti-Thrombin III, and it is effective in concentrations as low as 1 unit per ml of blood. Heparin has no ability to lyse preformed thrombi or fibrin sheaths and has no antibacterial properties. In fact, it may promote growth of bacteria within the “biofilm” layer of protein on catheter surfaces. Also, heparin induces severe loss of platelets and paradoxical clotting in some patients (the “white clot” syndrome). 
     Another anticoagulant used for catheter locking is urokinase, which is derived from urine and kidney cells. It is a serine protease composed of two chains joined by a disulfide bridge. The precursor molecule, single-chain urokinase (scu-PA) is also active. Urokinase is inhibited by plasminogen activator inhibitors 1 and 2, and protease nexin-1. A receptor for urokinase on endothelial cells (u-PAR) may modulate urokinase activity by removal of urokinase-plasminogen activator-inhibitor complexes. Both two-chain and single-chain urokinases are more active in the presence of fibrin and heparin. Catheter lumens maybe locked with urokinase to restore the patency of a clotted catheter, or urokinase may be used instead of heparin to prevent clot formation between dialyses. In case of inability to aspirate the locking solution, the injection of 10,000 units of urokinase is harmless, since much higher doses are used systemically to lyse fibrin sheaths formed on the outer surface of the catheter. 
     Another anticoagulant used for catheter locking is tissue plasminogen activator, which is a single-chain serine protease with a molecular weight of 68 Kda. Tissue plasminogen activator has not been used for routine locking of catheters, but has been used in small doses (1-2 mg) to restore patency of clotted catheter lumens. Injection of this small dose of tissue plasminogen activator present in the catheter lumen has no systemic effect. 
     Catheter Infections 
     Infection associated with catheters is a major reason for their removal. The major source of infection in cuffed catheters appears to be contamination of the catheter hub or lumen during connection or disconnection procedures at the start of and completion of hemodialysis. Periluminal migration of bacteria along the external surface of the catheter as a source of infection seems to be less common, since most catheter-associated bacteremias are not combined with exit or tunnel infection. The surfaces of catheters create a conducive environment at which bacteria can grow and impede phagocytosis by white blood cells. Furthermore, the bacteria can produce a biofilm, i.e., a coating of proteins and glycocalyx that protects bacteria from antibiotics and white cells. 
     None of the aforementioned anticoagulant locking solutions has any significant antibacterial properties and, therefore, none is of any assistance in combating or preventing infection. While it is possible to lock catheters with bactericidal agents, such as concentrated (27%) sodium chloride, 10% povidone iodine, 4% chlorhexidine, or 1% sodium hypochlorite, none of these bactericidal agents has any anticoagulant activity. 
     If systemic antibiotics are used for treating bacteremia, they will have an antibiotic action while they are present in the catheter, but this occurs only when blood is flowing through the catheter lumen, such as in dialysis. Treatment with systemic antibiotics is frequently ineffective and removal of the catheter becomes necessary, due to persistent bacteremia (caused by catheter colonization) or worsening clinical condition, Catheter removal, however, is not always possible due to the difficulty in creating alternative blood access. Infection also is the major reason for removal of the smaller cuffed central venous catheters used for infusion of drugs or total parenteral nutrition. Their internal surfaces may also be subjected to antibiotic agents, but only during antibiotic infusion. 
     One approach to salvaging a colonized catheter is the use of flush solutions, i.e., to lock the ports of the catheter with a mixture of an antibiotic and an anticoagulant or thrombolytic agent. The disadvantage of this method is the diffusion of small amounts of antibiotic into the systemic circulation. This may cause induction of resistant organisms, a growing concern for all antibiotics. For this reason, it is unlikely that the Food and Drug Administration (FDA) would approve chronic catheter locking with antibiotics, and the use of antibiotics for infection prophylaxis should be avoided. 
     Another approach is to use as a locking solution trisodium citrate, which may have both anticoagulant and antibacterial properties. However, while studies have indicated that concentrated trisodium citrate is able to kill or prevent the growth of most bacteria, it seems to have only a weak effect on staphylococcus aureus, which, of the most common microorganisms responsible for catheter-associated infections, is the most virulent and difficult to eradicate without catheter removal. Another disadvantage of catheter locking with concentrated citrate trisodium is its ability to induce transient hypocalcemia, tingling of the fingers and metallic taste when injected into the bloodstream even in small amounts. Even transient hypocalcemia may cause arrhythmia. 
     It would be possible to inject an anticoagulant agent into the catheter, followed by injection of a non-antibiotic bactericidal agent. However, diffusion would cause mutual dilution of both the anticoagulant agent and the bactericidal agent. Dilution of the anticoagulant should be avoided in order to prevent clot formation at the tip of the catheter. Also, diffusion of the solutions increases the risk of strong bactericidal agents being brought into contact with the blood, a condition which should also be avoided. 
     SUMMARY 
     As mentioned above, most data indicate that contamination of the catheter hub is the most common etiology of catheter-associated bacteremia. For prevention of intralumenal clot formation it is important to maintain the presence of an anticoagulant at the catheter tip. Thus, ideally, for antibacterial action, the catheter lumen should be filled with bactericidal solution in the external or proximal portion of the lumen (close to the hub), and for prevention of clotting should be filled with anticoagulant solution in the internal or distal part of the lumen (close to the tip). However, for the reasons explained above, the solutions should not mix. 
     Accordingly, a fundamental aspect of the invention is the locking of a catheter by the use of an anticoagulant agent and an antimicrobial agent with a separator therebetween. More specifically, the invention utilizes an air bubble to separate the anticoagulant and antimicrobial agents. 
     Another aspect of the invention is the use of a multi-chamber syringe for injection of the locking material into the catheter. 
     A further aspect of the invention is the use of such a multi-chamber syringe for aspiration of the locking material from the catheter. 
     A still further aspect of the invention is the provision of a unique multi-chamber syringe suitable for these purposes. 
     Certain ones of these and other aspects of the invention may be realized by providing a method of preserving the operative condition of an implanted vascular access catheter having inner and outer ends, between uses of gaining access to the vascular system of the patient, the method comprising: inserting an anticoagulant agent through the catheter outer end to drive any blood in the catheter back into the patient vascular system and to fill an inner portion of the catheter with the anticoagulant agent; then inserting a separating substance into the catheter to fill a central portion of the catheter; and then inserting an antimicrobial agent into the catheter to fill an outer portion of the catheter, whereby the separating substance separates the anticoagulant agent from the antimicrobial agent. 
     Other aspects of the invention maybe realized by providing a syringe comprising an external barrel having an end seal with a discharge opening therein and an internal barrel disposed within the external barrel and having plural separated chambers each having an outlet opening and a plunger, the internal barrel being movable relative to the external barrel among a closed condition wherein the outlet openings are in sealing engagement with the seal and plural injection conditions wherein the outlet openings are respectively disposed in communication with the discharge opening. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     For the purpose of facilitating an understanding of the subject matter sought to be protected, there are illustrated in the accompanying drawings embodiments thereof, from an inspection of which, when considered in connection with the following description, the subject matter sought to be protected, its construction and operation, and many of its advantages should be readily understood and appreciated. 
     FIG. 1 is a perspective fragmentary view of a catheter implanted in the intravenous system of a patient and locked in accordance with the invention; 
     FIG. 2 is a longitudinal sectional view of a two-chamber syringe in accordance with one embodiment of the invention; 
     FIG. 3 is an enlarged top plan view of the two-chamber syringe of FIG. 2; 
     FIG. 4 is an enlarged sectional view taken generally along the line  4 — 4  in FIG. 2; 
     FIG. 5 is an enlarged fragmentary view of a portion of FIG. 2; 
     FIG. 6 is an enlarged fragmentary view of the lower end of FIG. 2; 
     FIG. 7 is a view similar to FIG. 3 of another embodiment of the invention; 
     FIG. 8 is a top plan view similar to FIG. 4 of the embodiment of FIG. 7; 
     FIG. 9 is a cross sectional view of the syringe of FIG. 8 just above the bottom of the internal barrel; and 
     FIG. 10 is a view similar to FIG. 4, showing an alternative embodiment. 
    
    
     DETAILED DESCRIPTION 
     Referring to FIG. 1, there is illustrated a catheter  10  implanted in a vein  11  of a patient, the catheter having a distal or inner end or tip  12  disposed in the vein  11  and a proximal or outer end or hub  13 , disposed outside the patient&#39;s body. Also illustrated is a two-chamber syringe  20  in accordance with the invention, the details of which will be explained more fully below, which may be used in performing the method of the invention. The hub has a Y-connector  14  adapted for connection to a conduit set of associated apparatus, such as for performing dialysis or the like, in a known manner. When not in use, the catheter  10  is filled with a locking fluid and the Y-connector  14  is then closed off with a suitable closure. The present invention relates to a method and apparatus for effecting the catheter lock. 
     The lumen of the catheter  10  has a specific capacity provided by the manufacturer. To fill the entire catheter lumen, a measured volume of fluid will be used. In accordance with the method of the invention, approximately one-half of the lumen capacity will be injected with a solution of an anticoagulant agent  15  driving any blood in the catheter back into the patient&#39;s vascular system. Then, a separating substance, such as a small air bubble  16 , which may be about 0.1 ml in volume, will be injected, followed by injection of an antimicrobial agent  17 , such as a bactericidal solution of calculated volume to fill the remainder of the catheter lumen. Then the catheter is closed. In vitro experiments have shown that two solutions separated by an air bubble do not mix if left in glass tubes and agitated catheters for several weeks. Thus, the air bubble  16  is effective to maintain the presence of the anticoagulant agent  15  at the catheter tip, while maintaining the antimicrobial agent  17  in the outer portion of the catheter lumen, without fear of the two solutions mixing. Prior to the next catheter use, the locking substances are aspirated and the dialysis or infusion is started in a routine manner. 
     In current practice, in case of catheter blockage by a clot, frequently the locking solution cannot be aspirated and is, therefore, injected into the patient. As mentioned above, excessive anticoagulation or other side effects may result from such injection. The injection of bactericidal solution may cause even more severe side effects and, therefore, it is essential to aspirate bactericidal solution from the catheter lumen. In vitro experiments using the method of the invention, show that the bactericidal solution can be readily aspirated in clamped catheters, since the air bubble  16  readily expands at negative pressure. Once the bactericidal solution is aspirated, the external catheter lumen is clamped, a saline-filled syringe is attached and the saline injected and aspirated again. This maneuver may be repeated, as needed, to insure complete removal of the bactericidal solution. 
     Because many bactericidal agents if injected into a patient may have adverse affects, a preferred bactericidal solution may be acidified concentrated saline, specifically 27% NaCl acidified with HCl to a pH of 2.0. To achieve a pH of 2.0, 1 mL of concentrated (37%) HCl may be added to 1 L of concentrated (27%) NaCl, whereby 1 mL of bactericidal solution will contain 270 mg of NaCl and 0.37 mg of HCl. Such an acidified concentrated saline solution would have no adverse effects if injected into a patient. 
     While the locking substances may be injected into the catheter  10  by the use of any desired means, in one form of the invention the injection is effected by the use of a specially-designed multiple-chamber syringe, one such syringe being illustrated in FIGS. 2-6. The use of this syringe permits the locking solutions to be added with only a single connection to the catheter, which significantly decreases the chances of catheter infection. Referring to FIGS. 2-6, there is illustrated the two-chamber syringe  20  which has an external barrel  21  with an elongated cylindrical body  22 , provided at one end thereof with a radially outwardly projecting annular flange  23  having four equiangularly spaced notches  23   a  formed therein (see FIG.  4 ). The other end of the body  22  is closed by an end wall  24  which carries a Luer-lock tip  25 , which defines a discharge port  26 . The inner surface of the end wall  24  is covered with a seal  27  having a discharge opening  28  therethrough communicating with the discharge port  26  (FIG.  6 ). 
     The syringe  20  also includes an internal barrel  30  having a cylindrical outer wall  31  disposed coaxially within the external barrel  21  and in sealing engagement with the seal  29 . The inner end of the cylindrical outer wall  31  is closed by an end wall  32 . A diametrical septum  33  extends across the outer wall  31  along its entire length and divides it into two chambers  34  and  34 A. Formed in the end wall  32  are two outlet openings  35  and  35 A, respectively communicating with the chambers  34  and  34 A, and respectively provided with tips  36  and  36 A disposed in sealing engagement with the seal  27  (FIG.  6 ). A peripheral seal  29  is disposed along the outer surface of the lower end of the outer wall  31  and in sealing contact with the body  22  and with the seal  27 . The outer wall  31  is slightly longer than the external barrel  21  and projects upwardly therefrom. Integral with the outer wall  31  at its other end and extending radially outwardly therefrom is an annular flange  37  provided with four equiangularly spaced depending clips  38 . Each clip  38  has at its lower end a shoe  39  with a radially inwardly projecting tooth  39   a  dimensioned and positioned for engagement in a corresponding one of the notches  23   a  in the external barrel flange  23 , as can best be seen in FIGS. 4 and 5. The notches  23   a  and the teeth  39   a  may be generally V-shaped in transverse cross section so as to define slopping cam surfaces. The clips  38  have sufficient flexibility and resilience that the teeth  39   a  can be cammed out of the notches  23   a  to permit rotation of the internal barrel  30  relative to the external barrel  21 . 
     The chambers  34  and  34 A are respectively provided with plungers  40 ,  40 A, which may be substantially identical in construction. The plungers  40 , 40 A respectively have elongated bodies  41 ,  41 A made up of a plurality of interconnected flange walls  42 ,  42 A. The bodies are respectively provided at their inner ends with gaskets  43 ,  43 A and at their outer ends with handles  44 ,  44 A. 
     The Luer-lock tip  25  is disposed eccentrically of the external barrel end wall  24 , and the outlet openings  35  and  35 A of the chambers  34 ,  34 A are respectively positioned so that they can be brought into communication with the discharge port  26  by rotation of the internal barrel  30 . Before use, the internal barrel  30  is disposed in a closed or “neutral” position wherein neither outlet opening  35 ,  35 A is disposed in communication with the discharge port  26 , and both are sealed by the seal  27  and, more specifically, by tiny bulges  27   a  of the seal  27  which project upwardly slightly into the tip  36 ,  36 A (see FIG.  6 ). The chamber  34  is partially filled with a predetermined volume of an anticoagulant agent  15 , and a small volume, e.g., 0.1-0.2 ml, of air  16 . The chamber  34 A is filled with an antimicrobial agent  17 , such as a bactericidal solution. The Luer-lock tip  25  is then connected to the catheter  10  in a known manner and the internal barrel is rotated 90° so as to bring the outlet opening of the anticoagulant chamber  34  into alignment with the discharge port  26  and the discharge opening  28 . In this position, the teeth  39   a  of the clips  38  will again be engaged in the notches  23   a , serving as detents to prevent accidental movement of the internal barrel  30  from the selected position. The anticoagulant agent  15  and the airbubble  16  are then injected into the catheter  10 . Then, the internal barrel  30  is rotated 180° to bring the outlet opening of the other chamber  34 A into alignment with the discharge port  26 , whereupon the bactericidal agent is injected into the catheter  10 . The syringe  20  may then be disconnected from the catheter  10 , which may then be closed. 
     As was indicated above, the syringe  20  could also be used for aspiration of the locking fluids before the next use of the catheter  10 . Thus, for this purpose the syringe  20  would be connected to the catheter  10  as before, then the chamber  34 A would be rotated into alignment with the discharge port  26  for aspiration of the bactericidal solution  17 , the air bubble  16  simply expanding as the pressure is reduced. Then the internal barrel  30  would be rotated to bring the other chamber  34  into alignment with the discharge port for aspiration of the air bubble  16  and the anticoagulant agent  15 , whereupon the internal barrel  30  would be rotated to the closed or neutral position. 
     Referring to FIGS. 7-9, there is illustrated a three-chamber syringe  50  in accordance with another embodiment of the invention. The syringe  50  has an external barrel which may be substantially identical to external barrel  21 , described above, and an internal barrel  60  disposed coaxially within the external barrel  21 . The internal barrel  60  is similar to the internal barrel  30 , described above, and like parts bear the same reference numerals. The basic difference is that the internal barrel  60  has a Y-shaped septum  63  which divides the outer wall  31  into three chambers  64 ,  64 A, and  64 B, respectively having outlet openings  65 ,  65 A, and  65 B. The chambers  64  and  64 A are substantially the same size and shape and are much larger than the chamber  64 B. The chambers  64 , 64 A, and  64 B are respectively provided with similarly-shaped plungers  70 ,  70 A, and  70 B, which respectively have bodies made up of interconnected flange walls  72 ,  72 A, and  72 B, and respectively provided with gaskets (not shown) at their inner ends and handles  74 ,  74 A, and  74 B at their outer ends. 
     The syringe  50  has a neutral position wherein all of the outlet openings  65 ,  65 A, and  65 B are sealed, as illustrated in FIG.  9 . The chambers  64 ,  64 A, and  64 B are, respectively, filled with anticoagulant, bactericidal solution and air, and they are respectively moved into alignment with the outlet port  26  for sequential injection of these locking fluids into the catheter  10 . The syringe  50  may also be used for aspiration of the locking fluids from the catheter. 
     Referring to FIG. 10, there is illustrated a portion of an alternative syringe  80  which is similar to the syringe  20 , described above, except for the changes described below. The syringe  80  has an external barrel with a flange  81  which corresponds to the flange  23  of the syringe  20 , except that it is provided with notches  82  which, instead of being in the form of isosceles triangles, are in the from of right triangles, each having a non-radial cam surface  83  and a substantially radial stop surface  84 . The syringe  80  also has an internal barrel similar to the internal barrel  30 , except that it is provided with clips  85  respectively having teeth  86  shaped and dimensioned for mating engagement in the notches  82 . Thus, each tooth  86  has a cam surface  87  and a stop surface  88 . It will be appreciated that the shape of the notches  82  and the teeth  86  will permit rotation of the internal barrel in a clockwise direction, as viewed in FIG. 10, but will prevent rotation in a counterclockwise direction. With this embodiment, the contents of the chambers of the internal barrel can be arranged so as to be sequentially brought into position for proper sequential injection into the catheter when the internal barrel is rotated clockwise. The arrangement prevents counterclockwise rotation and, thereby, inhibits injection of the locking fluids in an incorrect order. It will be appreciated that a similar arrangement could be used with the three-chamber syringe  50 . 
     The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation. While particular embodiments have been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made without departing from the broader aspects of applicant&#39;s contribution. The actual scope of the protection sought is intended to be defined in the following claims when viewed in their proper perspective based on the prior art.