Methods and apparatus for monitoring and quantifying the movement of fluid

Abstract

Methods, systems and devices are provided for monitoring and quantifying the movement of fluid in a target region. Generally, an imaging agent is introduced into a target region through fluid flow. The imaging agent in the target region is then disrupted using appropriate methods such as the application of ultrasonic energy. As fluid flow brings undisrupted imaging agent into the target region, the rate of accumulation is monitored and quantified thereby providing the exchange rate and flow rate of the fluid in the target region. The disclosed invention is particularly useful for medical applications such as determining the flow rate of blood in an organ or tissue.

What is claimed is:  
     
         1 . A method for determining a rate of fluid exchange in a target region containing a known volume of fluid comprising the steps of: 
 introducing an intact contrast agent containing a fluorinated gas or vapor into a flowing bodily fluid such that the intact contrast agent is transported into the target region;    applying energy such that contrast agent is at least partially disrupted by the application of energy;    calculating the fluid exchange rate based on an observed rate at which intact contrast agent reinfuses the target region containing the known volume of fluid.    
     
     
         2 . The method of  claim 1 , wherein said target region comprises mammalian tissue.  
     
     
         3 . The method of  claim 1 , wherein said contrast agent comprises a microbubble contrast agent.  
     
     
         4 . The method of  claim 3 , wherein the contrast agent is disrupted by applying ultrasonic energy at a power level sufficient to destroy a portion of the microbubbles.  
     
     
         5 . The method of  claim 1 , wherein said fluorinated gas or vapor is selected from the group consisting of fluoroheptane, fluorocycloheptane fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethylcyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers, fluoropolyethers, fluorotriethylamines, sulfur hexafluoride and combinations thereof.  
     
     
         6 . The method of  claim 1 , wherein said fluorinated gas or vapor is perfluoropentane.  
     
     
         7 . The method of  claim 1 , wherein said fluorinated gas or vapor is perfluorohexane.  
     
     
         8 . The method of  claim 1 , wherein the observed rate of reinfusion is determined by emitting at least one ultrasonic pulse to measure one or more signal levels indicative of the concentration of intact microbubbles in said target region.  
     
     
         9 . The method of  claim 8 , wherein said signal levels are measured using a frequency different from the frequency of the emitted ultrasonic pulse.  
     
     
         10 . The method of  claim 8 , wherein signal levels indicative of the level of intact microbubbles in said target region are measured using a plurality of ultrasonic pulses.  
     
     
         11 . The method of  claim 1 , wherein the calculation of the fluid exchange rate comprises: 
 comparing at least two signal levels indicative of the concentration of intact imaging agent in said target region wherein the signal levels are measured at different times to ascertain the increase in signal per unit time;    dividing the increase in signal per unit time by a measured or derived maximum signal value to obtain the fluid exchange rate;    multiplying the obtained fluid exchange rate by the fluid content of said target region to obtain a perfusion rate for said target region.    
     
     
         12 . The method of  claim 11 , further comprising the step of determining the fluid content of said target region by comparing a signal level from said target region with a signal level obtained from a pure source of moving fluid comprising undisrupted imaging agent.  
     
     
         13 . The method of  claim 11 , wherein said fluid exchange rate is calculated by subtracting a signal level measured immediately following disruption of the contrast agent from a signal level measured at least 3 seconds following disruption of the contrast agent and dividing the result by the intervening time period.  
     
     
         14 . The method of  claim 1 , wherein the fluid exchange rate is calculated using the stirred tank dilution exponential equation: S(t)=Sp (1−exp(−tF/V))+So, where S(t) is the signal level after a preselected period, t is the preselected period and Sp, So and F/V are fitting parameters corresponding to the signal rise after an infinite period, the signal provided by disrupted imaging agent and the fraction of fluid exchanged each second respectively.  
     
     
         15 . A system for determining the rate of fluid exchange comprising: 
 a signal-generating ultrasound contrast agent;    an ultrasonic transducer capable of non-invasively disrupting at least a portion of the contrast agent present in a target region containing a known volume of fluid and observing a signal produced by the contrast agent upon insonation; and    a processor operatively linked to the transducer whereby said processor calculates the rate of fluid exchange in a target region based on transducer observed localized increases in contrast agent signal level following transducer mediated disruption of the contrast agent in the target region.    
     
     
         16 . The system of  claim 15 , wherein said ultrasound contrast agent comprises a microbubble contrast agent.  
     
     
         17 . The system of  claim 16 , wherein said microbubble contrast agent comprises a fluorinated gas or vapor.  
     
     
         18 . The system of  claim 17 , wherein said fluorocarbon gas or vapor is selected from the group consisting of fluoroheptane, fluorocycloheptane fluoromethylcycloheptane, fluorohexane, fluorocyclohexane, fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethylcyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorotrimethylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers, fluoropolyethers, fluorotriethylamines sulfur hexafluoride and combinations thereof.  
     
     
         19 . The system of  claim 18 , wherein said fluorocarbon gas or vapor is perfluoropentane.  
     
     
         20 . The system of  claim 18 , wherein said fluorocarbon gas or vapor is perfluorohexane.  
     
     
         21 . The system of  claim 15 , wherein said processor calculates the fluid exchange rate based on a plurality of measured signal levels obtained over time from the target region.  
     
     
         22 . The system of  claim 15 , wherein said processor calculates the fluid exchange rate by: 
 comparing at least two observed signal levels indicative of the concentration of intact imaging agent in said target region wherein the signal levels are measured at different times to ascertain the increase in signal per unit time;    dividing the increase in signal per unit time by a measured or derived maximum signal value to obtain the fluid exchange rate.    
     
     
         23 . The system of  claim 15 , wherein the processor calculates the fluid exchange rate by subtracting a signal level corresponding to a baseline frame from at least one signal level corresponding to a subsequently obtained interrogative frame and dividing the result by the intervening time period.  
     
     
         24 . The system of  claim 15 , wherein the processor calculates the fluid exchange rate using the stirred tank dilution exponential equation: S(t)=Sp (1−exp(−tF/V))+So, where S(t) is the signal level after a preselected period, t is the preselected period and Sp, So and F/V are fitting parameters corresponding to the signal rise after an infinite period, the signal provided by disrupted imaging agent and the fraction of fluid exchanged each second respectively.  
     
     
         25 . The system of  claim 15 , wherein said processor further calculates a fluid perfusion rate in the target region.  
     
     
         26 . The system of  claim 15 , further comprising a timer operably associated with said processor.  
     
     
         27 . A device for non-invasively determining the rate of fluid exchange comprising: 
 an ultrasonic transducer capable of non-invasively disrupting at least a portion of an ultrasound contrast agent present in a target region containing a known volume of fluid and observing a signal produced by the contrast agent upon insonation to provide a plurality of ultrasound images;    a digital storage medium operably associated with said ultrasonic transducer wherein said digital storage medium receives data representative of said plurality of ultrasound images from the transducer; and    a processor operably associated with the digital storage medium whereby said processor calculates the rate of fluid exchange in the target region based on measurable differences in the ultrasound image data obtained from the digital storage medium.    
     
     
         28 . The device of  claim 27 , wherein said processor calculates the fluid exchange rate based on a plurality of measured signal levels obtained over time from the target region.  
     
     
         29 . The device of  claim 27 , wherein said processor calculates the fluid exchange rate by: 
 comparing at least two observed signal levels indicative of the concentration of intact imaging agent in said target region wherein the signal levels are measured at different times to ascertain the increase in signal per unit time; and    dividing the increase in signal per unit time by a measured or derived maximum signal value to obtain the fluid exchange rate.    
     
     
         30 . The device of  claim 27 , wherein the processor calculates the fluid exchange rate by subtracting a signal level corresponding to a baseline frame from at least one signal level corresponding to a subsequently obtained interrogative frame and dividing the result by the intervening time period.  
     
     
         31 . The device of  claim 27 , wherein the processor calculates the fluid exchange rate using the stirred tank dilution exponential equation: S(t)=Sp (1−exp(−tF/V))+So, where S(t) is the signal level after a preselected period, t is the preselected period and Sp, So and FN are fitting parameters corresponding to the signal rise after an infinite period, the signal provided by disrupted imaging agent and the fraction of fluid exchanged each second respectively.  
     
     
         32 . The device of  claim 27 , wherein said processor further calculates a fluid perfusion rate in the target region.  
     
     
         33 . The device of  claim 27 , further comprising a timer operably associated with said processor.  
     
     
         34 . The device of  claim 27 , wherein said processor comprises a personal computer.  
     
     
         35 . The device of  claim 27 , further comprising a display operably associated with said processor.