Modeling of pharmaceutical propagation and parameter generation

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The following information is provided to assist the reader in understanding some of the environmental technology and this technology can be used as described below. Used herein is not intended to be limited to any particular narrow interpretation unless clearly indicated otherwise in this document. References described herein may facilitate understanding of the background of technology or. The disclosures of all references cited herein are incorporated by reference.

In order to radiologic contrast agent administered (for example, a power injector), usually to an empty disposable syringe filled with drugs specific volume of contrast agent from the beginning clinician. In other operations, the use of contrast agents preloaded syringe. Clinician then determines to be administered to a patient a contrast agent volumetric flow rate and volume, in order to achieve a diagnostic image. After administration of the contrast agent into a vein or artery, often injected with saline solution and the volume flow rate of the operator-determined. Many currently available syringe programmed to allow an operator to deliver a plurality of volumetric flow rate and volume of the discontinuous phase. For example, SPECTRIS SOLARIS® and STELLANTl® syringe (available from Medrad, Inc.0f Indianola, Pennsylvania where Virginia) and allowed to enter up to 6 including six or discontinuous phase of a patient for delivery to the volumetric flow rate and volume (e.g., contrast agent and / or saline). Such syringes and injector control program for use therewith are disclosed in, e.g., U.S. Patent No. 6,643,537 and U.S. Patent Application Publication No. 2004-0064041, the disclosures of which are incorporated herein by reference. For each type of operation and for each vaccination / imaging operation of patients, or parameter values ​​within this phase, usually manually entered by the operator. Alternatively, you can manually enter the values ​​stored earlier volume and flow rate, and subsequent calls from computer memory in. However, to determine such parameters for a particular way of operating a particular patient is still in development.

In this regard, it has been recognized that differences in quantitative imaging and other operations of different patients required administration of contrast agent. For example, U.S. Patent No. 5,840,026 (the disclosure of which is incorporated herein by reference) discloses a device and method for injection prior to use or patient-specific data obtained during injection of the patient to customize injection. Although recognized based on differences in patient dosing medical imaging operation requirements vary, but a conventional medical imaging operation is still continuing medical imaging operation using a predetermined standard dose for injection of contrast medium or delivery programs. Taking into account including MDCT (or MSCT) scanner, including the recently available CT scanners scanning speed increases, than in the area of ​​single-phase injection using this fast scanner in the two-phase injection or other multi-phase injection. Although the use of a standard, fixed or predetermined delivery scheme (either single-phase, two-phase or multi-phase) will simplify the operation, but in the same program to provide the same amount of contrast medium to the patient may produce different image contrast and quality very different results. Further, by introducing new MDCT scanners, in clinical practice and in the literature of CT is an open question: criteria for comparing with the monolithic program, for use with the helical scanner if it will preferably move the machine for use MDCT operation.

Several studies have attempted CT angiography (CTA) in the quantitative analysis of the injection process, and is expected to improve arterial enhancement. For example, Bae and colleagues developed a contrast agent pharmacokinetic behavior of the drug (PK) model, and solve the system of coupled differential equations, which aims to find the artery leading to the most uniform enhanced driver function. KTBae, JPHeiken, and JABrink, "aorta and hepatic contrast medium enhancement atCT.Part 1.Prediction with a computer model ,,, Radiology, vol. 207, p. Section 647-55 (1998); Κ.T.Bae," Peak contrast enhancement in CT and MR angiography:? when doesit occur and why Pharmacokinetic study in a porcine model ,,, Radiology, vol. 227, p of 809-16 (2003); Κ.T.Bae et al., "Multiphasic Injection Method for UniformProlonged Vascular Enhancement at CT Angiography: Pharmacokinetic Analysis andExperimental Porcine Method, "Radiology, vol. 216, para. 872-880 pages (2000); US Pat. No. 5,583,902,5, 687,208,6, 055, 985,6, 470,889 and 6,635,030, the disclosures of which are incorporated herein by reference. Group simplified compartment model of differential equations described by Bae et al inverse solution indicator: the contrast agent flow rate decreases exponentially CT imaging operation can lead to optimal / constant enhancement. However, inverse solution PK model by calculating the injection is most CT survey line without significant power injector can not be easily modified to achieve the survey line.

In Bae model does not consider realization PK model in the controller frame. For example, when the differential equation system is converted to state-space form, the resulting state matrix of rank less than the order of the system, this is because the number of free parameters in the system formula. When trying to reverse the matrix, the rank deficiency will it show itself as a singularity, and for digital representation used to predict and control system is problematic in terms. In addition, Bae model can not solve the transport delay of contrast agents directly, but through the introduction of multiple series of sub-compartment model to cardiopulmonary modeling of transport delays. Said plurality of sub-compartments can provide an analog output propagation delay, because the new phase response of the system is different (accumulated), due to the additional compartment. Introducing multiple compartments is somewhat arbitrary, even if based on physical insight into the vascular system. For example, lung compartment is divided into 30 sub-compartments, because the contrast agent bolus dispersion and delay in cardiopulmonary system.

Wada and Ward's "The hybrid model: a new pharmacokinetic model forcomputer-controll ed infusion pumps ,,, IEEE Trans.Biomed Eng, 41 (2), pp. 134-142, 1994 (the disclosures by incorporated herein by reference), derived Bee and methods employed similar three compartment pharmacokinetic model, and the model is used to control the program, attempts to adjust to the plasma concentration of anesthetic (load dilution, uploadalienating). They are attempt to contrast agent recirculation effects modeling of blood flow through, and in which they are delayed by the transport into its simulation and modeling of blood flow, they can produce an analog prediction error is less than 5%.

Wada and Ward "Open loop control of multiple drug effects inanesthesia", IEEE Trans.Biomed Eng, 42 (7), pp. 666-677, 1995 also apply them The pharmacokinetic (PK) model to control a variety of effects of narcotic drugs. Their control scheme requires anesthesiologists to set the allowable level of side effects (expressed as a plasma concentration).

In another embodiment, Fleischmann and colleagues cardiovascular physiology and kinetics of contrast agent as a "black box", and quickly pushed through with a short contrast agent injection (approximate per pulse) forced the system to determine its impulse response (impulseresponse). In this method, the Fourier transform of the impulse response, and to manipulate the transfer function estimate, to determine practice better than the previous injection trajectory estimation. D.Fleischmann and K.Hittmair, "Mathematical analysisof arterial enhancement and optimization of bolus geometry for CT angiographyusing the discrete Fourier transform ,,, JComput Assist Tomogr, vol. 23, pp. 474-84 (1999), the disclosure of which is incorporated by reference incorporated herein.

Single-phase administration of the contrast agent (usually, 100-150mL contrast agent, in a flow rate) will lead to non-uniform enhancement curve. See, for example, D.Fleischmann and K.Hittmair, supra; and KTBae, "Peakcontrast enhancement in CT and MR angiography: when does it occur and why Pharmacokinetic study in a porcine model, '' Radiology, Vol. 227, 809? -16 (2003), the disclosures of which are incorporated by reference herein .Fleischmann and Hittmair thus proposed a scheme that attempts to regulate the administration of the contrast agent to be suitable for two-phase injection of a single patient, in order to optimize the aorta imaging control CT contrast agent exhibits a fundamental difficulty is hypertonic drug quickly diffused from the central blood compartment. In addition, blood mixed with contrast medium without contrast agent, which was diluted.