INTRAVENOUS DRUG ADMINISTRATION APPARATUS

Abstract: An intravenous drug administration apparatus which automatically delivers a drug with an exponentially decreasing concentration from a high loading concentration down to a patient maintenance concentration followed by continued infusion at the maintenance concentration rate. The apparatus includes a large container, such as an intravenous solution bag, which holds the low maintenance concentration, and a smaller vessel containing the high loading concentration. The low concentration solution is passed from the large volume container into the lower end of the smaller vessel so as to obtain a continuous mixing action within the vessel, and the mixed and progressively diluted solution is continuously removed from the vessel for delivery and infusion to the patient. The inlet to the vessel may be provided by a short length hypodermic needle and the outlet by a long length hypodermic needle which extends into the upper portion of the vessel. This apparatus has been found highly effective for the delivery of lidocaine, an anti-arrhythmic drug.

Description: INTRAVENOUS DRUG ADMINISTRATION APPARATUS BACKGROUND AND PRIOR ART Intravenous solutions, such as saline or glucose solutions, are often used as carriers for the continuous administration of drugs to patients at controlled infusion rates. The drugs may be prepackaged in intravenous solution bags or bottles. The drug-containing intravenous solution may be administered by gravity flow, using a drip chamber and rate control volve, or a drip chamber with automatic rate controller. Infusion pumps may also be employed which can be preset to provide a constant solution volume delivery rate, and thereby a selected rate of the drug dissolved in the intravenous solution at a preestablished concentration. A constant rate drug infusion apparatus, as described above, is not a clinically adequate administration means for drugs where a rapid achievement of therapeutic level is needed followed by the maintenance of a highly critical serum.level to obtain therapeutic effectiveness over a long period of administration without adverse side effects. Bolus injections of the drug can be used to provide a rapid serum concentration followed by a constant rate infusion, but the transition period between the loading injection and the achievement of a-stable serum level at the desired therapeutic concentration is not effectively controlled. A rapid injection followed by a constant slow rate infusion has the disadvantage that there is a considerable time during the early hours when the plasma concentrations are sub-therapeutic. A staged infusion has therefore been proposed and used to some extent, a fast constant infusion being used following the loading injection, and then by a slow constant infusion. Multiple further rapid injections may also be used to augment a slow constant infusion. All of these procedures have the disadvantages that they require attention at strictly defined times if the plasma concentra- tion is not to rise to a toxic level or to a level giving undesired side effects, or, on the other hand, to fall to a sub-therapeutic level. When a drug is administered intravenously the early plasma drug concentrations are much higher than the drug concentrations in tissues with a poor blood supply. With time the drug distributes to these other tissues and a steady state of distribution is reached. Once this dis¬ tribution in the body has reached steady state, the aim is to maintain the steady state of infusing drug at the same rate at which it is eliminated from the body. The problem of developing a simple apparatus for optimu intravenous drug administration has been particularly studie in connection with the administration of anti-arrhythmic drugs such as lidocaine. The effectiveness of lidocaine depends on the rapid achievement and maintenance of rather narrow therapeutic plasma levels, viz. 1.5 to 5.5 micrograms milliliter. Concentrations above the critical range have been associated with toxic effects including convulsions, coma, and respiratory arrest, while lower concentrations do not adequately protect the patient against a life- threatening arrhythmia. See Salzer, et al, Clin. Pharmacol. Ther. , 29 (5) 617-624 (1981); and Stargel, et al, Amer. Heart J. , 102 872-876 (1981) . It has been proposed that the ideal transitional infusion between a loading injection and a constant rate infusion would be an exponentially decreasing drug infusion rate. This has been approximated by using mechanical constant rate infusion pumps and stepped decreases in the delivery rate. See Vaughn, et al, Europ. J. Clin. Pharmacol. 10, 433-440; and Loo, et al, J. Pharm. Scic, 57, 918-928 (1968). - SHEgfr OMPI •Dilutional methods for achieving an exponentially decreasing delivery rate for lidocaine or other drugs have been tested with experimental animals. Boyes, et al, J. Pharmacol. Exp. Ther. , 174, 1-8 (1970; and Foulkes, J. Pharmacol. Exp. Ther. , 150, 406-413 (1965). As describe in these references, an intravenous solution containing no drug is used for progressive dilution of a solution containing the drug. The solutions were mixed by a magnetic or mechanical stirrer. The diluted mixture was delivered to experimental animals. While this procedure is highly desirable from a theoretical standpoint, no simple practical apparatus has heretofore been developed which safely and automatically achieves an exponentially decreasing concentration of the drug. SUMMARY OF INVENTION The intravenous drug administration apparatus of this invention provides in a simple and automatic manner a first administration phase in which the drug is infused at an exponentially decreasing concentration from a high loading concentration down to a maintenance concentration, and a second phase in which there is continued delivery of the low maintenance concentration. Observation and resettings are minimized. The patient may be given one or more loading injections, such as for the administration of lidocaine as anti-arrhythmic drug, and then the infusion is started to automatically provide the exponentially decreasing phase during the transitional period while the drug is distribu¬ ting from the blood into the tissues, and thereafter the maintenance concentration being adequate to replace the drug as it is eliminated from the body. The apparatus includes a closed container with a first sterile intravenously administerable carrier containing the drug at a low patient maintenance concentration. There is also a closed rigid mixing vessel of smaller volume having a second sterile intravenously administerable carrier containing the drug at a high loading concentration. The smaller vessel functions as a mixing vessel, and is provided with inlet and outlet means constructed and arranged to provide a mixing action within the vessel. The inlet is connected to the larger volume low concentration carrier, and the outlet to the infusion cannula connected to the patient. In a preferred arrangement, hypodermic needles are employed to provide the inlets and outlets for the mixing vessel, a short needle extending into the lower portion of the vessel and functioning as the inlet, and a long needle extending into the upper portion of the vessel and providing the outlet. In a preferred application, the drug in the solutions of the apparatus is lidocaine. However, the apparatus is adaptable for use with many other drugs which are capable of being administered intravenously in aqueous solutions. THE DRAWING The apparatus of this invention is shown in an illustra tive embodiment in Fig. 1 of the attached drawing. It shoul be understood that certain of the components of the apparatus are shown diagramatically because of their well- known construction, and that the relative size of the apparatus components, such as the solution bag and the mixing vessel can be varied widely and are not necessarily shown to scale in the drawing. DETAILED DESCRIPTION The intravenous drug administration apparatus of this invention utilizes as one of its components, a closed container with a first sterile intravenously administerable aqueous solution therein. This container may be a standard intravenous solution bag or bottle containing 0.5 or 1.0 liters of an intravenous solution, such as a normal saline solution, a glucose solution, etc. The drug to be administered is dissolved in the intra¬ venous solution at a low maintenance concentration. For example, the drug may be lidocaine dissolved in the amount of 2,000 mg in 1,000 ml of normal saline, giving a con¬ centration of 2 mg/ml. Other anti-arrhythmic drugs such as mexiletine can be administered, as well as drugs for other conditions. For example, the apparatus may be used for the administration of an anaesthetic agent such as etho- hexitone, a respiratory stimulant such as doxapram, a drug for " premature labor such as ritodrine or salbutamol, a drug for acute asthmatic attacks such as theophylline, etc. The large volume container providing a solution of the drug at the low maintenance concentration will have an outlet positionable at the bottom thereof for gravity outflow, as is well known with respect to intravenous solution bags and bottles. A container may be provided with an inlet port for introduction of the drug, or the drug may be prepackaged in the container. The apparatus also includes a closed rigid mixing vessel of smaller volume having a second sterile intra¬ venously administerable aqueous solution providing a high loading concentration of the drug. Typically, the intra¬ venous solution will be the same as that in the larger volume container, that is, it will be a saline solution, a .glucose solution, etc., and the same drug will be dissolved in the second solution but at a considerably higher concentration, the concentration corresponding to a high loading concentration of the drug, as desired for an initial infusion of the patient. For example, where the drug is lidocaine and a normal saline solution is used, the mixing vessel and the solution therein may have a volume 5 of 20 ml and may contain 200 mg lidocaine, giving a concentration of 10 mg/ml. It will be understood that the relative concentrations and relative volumes of the first and second solutions are subject to wide variations, depending on the particular drug being administered, and 10 the desired length of the period of administration. However, in general, the loading concentration in the second solution will be at least three times that of the maintenance concentration in the first solution, and the volume of the first solution will be at least five 5 times that of the second solution. The mixing vessel is provided with an inlet connected to the container outlet by conduit means, and the inlet means is designed to provide a solution mixing action 20 within the vessel. The vessel is also provided with outlet means .positioned and arranged with respect to the inlet means so that mixing of the solutions can occur within the vessel for discharging an admixed solution to the outlet. A delivery conduit is connected to the outlet 25 for intravenous delivery of the admixed progressively diluted solution to a patient during a first phase of the administration. In the second phase, with the continued administration of the maintenance solution no mixing dilution is needed. The concentration of the drug in the 30 solution of the mixing vessel is at the same level as that of the larger volume container. The apparatus can be operated entirely by gravity flow. The container with the low concentration drug is 5 positioned at a higher level than the mixing vessel, and the solution is permitted to flow therefrom and into the mixing vessel under the action of gravity. However, it may be preferred to employ a constant rate pump. The pump may be preset to a desired flow rate, and interposed between the container and the mixing vessel. The low concentration solution is delivered from the outlet side of the pump to the mixing vessel. Several suitable pumps are commercially available, such as the Abbott/Shaw Life Care Pump. (See also U.S. patent 3,620,650). Other standard components of intravenous administra¬ tion sets will preferably be included. For example, a drip chamber and a rate control clamp, such as roller clamp, may be interposed between the low concentration container and the mixing vessel. Other commonly employed devices can be used, such as automatic rate controller to assure the maintenance of a constant drip rate. There will also usually be provided a shut off clamp on the downstream conduit between the mixing vessel and the cannula attached to the patient. A representative assembly of the components referred to above, including those especially adapted for perfor- ing the method of the present invention, are shown in the accompanying drawing. Fig. 1 is shown in somewhat diagramatic form and it should be understood that the components are not to exact scale. The intravenous solution bag, as shown, which contains the low concentra- tion solution of the drug, is provided with a hanger for mounting it at a level above, the mixing vessel to provide for gravity flow between the solution bag and the mixing vessel. In the illustration given, the bag has a lower outlet tube connecting to a drip chamber, which in turn is connected to the inlet of the mixing vessel by a conduit, which is provided with a roller clamp to provide for the drip rate adjustment. The lower end of the solution bag is also provided with an access port tube OMPI through which a drug may be introduced into the intra¬ venous solution within the bag. Preferably, however, the drug is prepackaged, in which case an access port will not be needed. As shown in the drawing, a con¬ ventional drip chamber is provided below the intra¬ venous solution bag, and connected by a conduit to the mixing vessel. A roller clamp may be mounted on the conduit adjacent the drip chamber for adjusting the drip rate, and thereby predetermining the constant flow rate. Alternatively, as described above, an automatic controller can be used. Further, as indicated by the dotted lines, a constant rate pump may be interposed in the conduit for passing the solution into the mixing vessel at a constant preset rate. The mixing vessel will contain the sterile aqueous solution of the drug at a high concentration corresponding to the desired loading concentration. In the illustration given, the mixing vessel consists of a small bottle or vial, having a rubber closure plug through which extend two hollow needles, a short inlet needle and a long outlet needle. The plug with the needles frictionally held therein is secured in the neck of the vial by means of a metal clamping ring. The needles may comprise commerciall available standard hypodermic needles, or special mixing needles may be designed for this application. The inlet needle, as shown, terminates in the lower portion of the mixing vessel, while the outlet needle extends into and receives solution from the upper portion of the vessel. With this arrangement, mixing action occurs within the vessel. The solution introduced through the inlet needle enters as a fine stream jet, which promotes mixing and turbulence within the vessel. Since the ends of the inlet and outlet needles are separated, mixing can occur within the vessel, so that an admixed solution is dis- OMPI charged through the outlet needle. The outer end of the outlet needle is connected to a conduit for delivery to the venous cannula of the patient. As shown, a slide clamp is mounted on the outlet conduit, which may be moved from an open position to a clamping position cutting off the flow. With the apparatus as shown in Fig. 1, after the patient has been given one or more injections of the drug to product immediate loading, the slide clamp may be opened to permit the beginning of the infusion. At the start of the infusion, the drug will be administered at the high concentration of the mixing vessel. As the administration proceeds, the low concentration solution from the bag will progressively mix with and dilute the solution in the mixing vessel, thereby providing a close approximation to an exponentially reducing concentration as delivered to the patient. Since the volume of solution in the bag is much greater than that in the mixing vessel, a condition will be reached at which there is remaining solution in the bag, while the concentration of the solution in the mixing vessel is the same as that of the bag. Thereafter, the continued administration will be at the low maintenance concentration of the bag solution. During all phases of the administration, there will be a minimal need to monitor or attend the administration apparatus. The transitional infusion with exponentially reducing concentration and the continued infusion there¬ after at the maintenance rate will be achieved automati¬ cally. In an illustrative embodiment, a one liter intravenou solution bag containing 0.9% saline can be used. 10 ml lidocaine HCL (200 g/ml) is introduced into the bag by an additive syringe, resulting in a lidocaine HCL con¬ centration of 2 mg/ml (1.7 mg/ml lidocaine). The mixing OMPI vessel can consist of a 20 ml vial of prepackaged lido- c caine solution containing 200 g lidocaine HCL (8.7 mg/ml lidocaine) . The vial may have a rubber closure through which hypodermic needles are inserted. The vial closure is pierced with two needles, the needle providing the inlet being 1/2" x 27 SWG hypodermic needle, and the 0 outlet being provided by a 1 1/2" x 22 SWG hypodermic needle. The inlet needle terminates in the lower portion of the inverted container, and the outlet needle extended into the upper portion, in the manner illustrated in Fig. 1. Preferably, although not essentially, the mixing vessel is completely full of solution, thereby elimina¬ ting any air space which might create air bubbles in the infusion solution. In a delivery rate experiment, a constant rate pump was interposed in the conduit between the solution bag and the mixing vessel. The dye indocyanine green was sub¬ stituted for the lidocaine at the same concentrations. The pump was set to deliver solution at a rate of 1 ml/ min. As the solution jetted into the mixing vessel throug the inlet needle, a mixing action was created, and mixed solution was continuously removed at the same rate through the outlet needle. The dye concentration as determined spectrophotometrically fell from 10 mg/ml to the concen¬ tration of 2 mg/ml by a close approximation to a pre- dieted exponential reduction curve. After 15 minutes the concentration of the delivered solution had fallen to 5.6 mg/ml (predicted 5.8), after 30 minutes to 2.3 mg/ml (predicted 2.4) after 90 minutes to 2.0 mg/ml (predicted 2.1), and after 120 minutes continued at 2.0 mg/ml (predicted 2.0 mg/ml). In use of the apparatus, total delivery time will depend on the volume of the low concentration solution. For example, with a 1 liter volume and a flow rate of 1 ml/min infusion can run for approximately 16.7 hours. At the same rate with a low concentration solution volume of 0.5 liters, the infusion can be continued for approximately 8.3 hours. In commercial embodiments of the apparatus of this invention, it will be preferred to have the drug pre¬ packaged in both the intravenous solution bag and in the mixing vessel. Further, the mixing vessel may be provided in the form of a vial equipped with a previously described inlet and outlet hypodermic needle. Closure caps may be provided for the projecting ends of the needles, which can be removed to permit their attachments to the appropriate conduits. Both the bag and the mixing vessel may be supplied as components of a complete intra¬ venous administration set.

Claims: CLAIMS I claim: 1. Intravenous drug administration apparatus, comprising a closed container with a first sterile intravenously administerable aqueous carrier therein, said carrier having an intravenously administerable drug therein at a low maintenance concentration, said container having an outlet positionable at the bottom thereof for gravity outflow, a closed rigid mixing vessel of smaller volume than said container having a second sterile intravenously administerable aqueous carrier providing a high loading concentration of said drug, said vessel having inlet means connected to said container outlet by conduit means, said inlet means providing a solution mixing action within said vessel, said vessel having outlet means positioned and arranged with respect to the inlet means so that mixing of said carriers can occur within said vessel for discharging an admixed carrier to said outlet means, and delivery conduit means connected to the outer end of said outlet means for intravenous delivery of the admixed carrier to a patient, whereby there can be delivered in a first administration phase an exponentially decreasing concentration of said drug from said high loading concentration down to said maintenance concentration, and in a second phase a continued delivery of said low maintenance concentration. 2. The apparatus of claim 1 in which said drug is lidocaine. 3. The apparatus of claim 1 in which said drug is lidocaine and said carriers are normal saline solutions, O PI 4. The apparatus of claim 1 in which said first carrier is supplied to said mixing vessel entirely by gravity flow. 5. The apparatus of claim 1 in which said inlet means comprises a hollow needle terminating in the lower portion of said vessel and said outlet means comprises a hollow needle having its inlet end located in the upper portion of said vessel. 6. The apparatus of claim 1 in which said loading concentration is at least three times that of said mainten¬ ance concentration, and said first carrier has a volume at least five times that of said second carrier. 7. Intravenous drug administration apparatus, comprising a closed container with a first sterile intravenously administerable aqueous solution therein, said solution having an intravenously administerable water-soluble drug dissolved therein at a low maintenance concentration, said container having an outlet positionable at the- bottom thereof for gravity outflow, a closed rigid mixing vessel of smaller volume than said container having a second sterile intra¬ venously administerable aqueous solution providing a high initial loading concentration of said drug, said loading concentration being at least three times that of said maintenance concentration, said first solution having a volume at least five times that of said second solution, said vessel having inlet means connected to said container outlet by conduit means, said inlet means providing a solution mixing action within said vessel, said vessel having. outlet means positioned and arranged with respect to the inlet means so that mixing of said solutions can occur within said vessel for discharging an admixed solution to said outlet means, and delivery conduit means connected to the outer end of said outlet means for intravenous delivery of the admixed solution to a patient, said first solution being supplied to said mixing vessel entirely by gravity flow, said inlet means comprising a hypodermic needle terminating in the lower portion of said vessel, and said outlet means comprising a hypodermic needle having its inlet end located in the upper portion of said vessel, whereby there can be delivered in a first administration phase an exponentially decreasing concentration of said drug from said high loading concentration down to said mainten¬ ance concentration, and in a second phase a continued delivery of said low maintenance concentration. 8. The apparatus of claim 7 in which said drug is lidocaine. 9. The apparatus of claim 7 in which said drug is lidocaine and said solutions are normal saline solutions. " EX Γ O PI

Inventors: RIDDELL JAMES GRAY, RIDDELL, JAMES, GRAY
Applicants: UNIV VANDERBILT, THE VANDERBILT UNIVERSITY
Application year: 1984
Main classification: A61M5
IPC codes: A61M5, A61M39