Abstract:
A method for detecting a complete or partial obstruction in a vessel through an intervening fluid includes receiving spectroscopic responses at different locations of a vessel wall, e.g., a vein or artery, through an intervening fluid, preferably blood. Spectroscopic responses are generated by irradiating the vessel wall at different locations and detecting spectra at those locations. In preferred embodiments, the radiation used is in the near infrared (NIR) region of the electromagnetic spectrum. The thrombus is located by determining whether fluctuations, spatial and/or spectral, of the spectral responses are indicative of thrombus.

Description:
BACKGROUND OF THE INVENTION 
     Intra luminal spectroscopic analysis devices have been developed and commercialized. One application concerns the assessment of the state of blood vessel walls such as required in the diagnosis of atherosclerosis. This is an arterial disorder involving the intimae of medium- or large-sized arteries, including the aortic, carotid, coronary, and cerebral arteries. Atherosclerotic lesions or plaques can contain complex tissue matrices, including collagen, elastin, proteoglycans, and extracellular and intracellular lipids with foamy macrophages and smooth muscle cells. In addition, inflammatory cellular components (e.g., T lymphocytes, macrophages, and some basophiles) can also be found in these plaques. 
     The intra luminal spectroscopic analysis devices are used to extract information concerning the state of the vessels walls from the generated spectral information. Mathematical and statistical manipulations such as linear and non-linear regressions of the spectral band of interest and other multivariate analysis tools are available for building quantitative calibrations as well as qualitative models for discriminant analysis, enabling the detection and characterization of any vascular lesions. 
     One specific intra luminal spectroscopic analysis device uses an optical source, such as a tunable laser, to access or scan a spectral band of interest, such as a scan band in the near infrared of 750 nanometers (nm) to 2.5 micrometers (μm). The generated light is used to illuminate tissue in a target area in vivo using a catheter. Diffusely reflected light resulting from the illumination is then collected and transmitted to a detector system, where a spectral response is resolved. 
     This intra luminal spectroscopic device actually builds a “color picture” of the inner walls of the blood vessel. This is accomplished by rotating the head of the catheter while drawing the head through the region of interest of the vessel. This produces the spectral response within the scan band of the tunable laser for a series of points along a helical path across the vessels walls. These points are aligned into a raster image of the vessel wall for the region of interest. 
     Another potential problem associated with vessels is the formation of thrombus. A thrombus or blood clot is a product of coagulation within a blood vessel and typically appears as a semisolid mass, with the thrombus impeding or blocking the flow of blood through the vessel. Typically it includes platelets, red blood cells, white blood cells and/or fibrin. Thrombosis, i.e., the formation or presence of a clot or thrombus, can be caused by infection, trauma, injury, a slowing down or stagnation of blood flow past a point of injury, or rupture of an atherosclerotic plaque. In fact, disruption or rupture of atherosclerotic plaques appears to be the major cause of heart attacks and strokes, because, after the plaques rupture, local obstructive thromboses form within the blood vessels. Both venous and arterial thrombosis can occur. A coronary thrombus often initially forms at the site of rupture of a vulnerable plaque; i.e. at the location of a plaque with a lipid-rich core and a thin fibrous cap (thin-cap fibroatheroma or TCFA). Thus, locating a thrombus can help find the culprit lesion, a task that is difficult using the current practice of angiography when the lesion is non-stenotic. Approaches for managing thrombosis include treatment with anticoagulants and/or medication designed to dissolves the clot, bed rest or surgical removal. 
     SUMMARY OF THE INVENTION 
     The invention generally relates to detecting a complete or partial obstruction in a vessel through an intervening fluid. In one example, the obstruction is a thrombus. In vivo location of a thrombus is useful during diagnosis, in monitoring response to medication, and in surgical procedures. 
     In one aspect of the invention, locating a thrombus includes receiving spectroscopic responses of a vessel wall, e.g., a vein or artery, through an intervening fluid, preferably blood. Saline solution or another suitable fluid also can be employed. 
     Spectroscopic responses are generated by irradiating the vessel wall at different locations and detecting spectra at those locations. In preferred embodiments, the radiation used is in the near infrared (NIR) region of the electromagnetic spectrum. As used herein, NIR refers to electromagnetic radiation in the wavelength region of about 700 nanometers (nm) to about 3000 nm. 
     In some implementations, the spectral response is first acquired for a full spectral region and then bands selected within the full spectral region for further analysis. NIR can be generated by a tunable laser. 
     In general according to one aspect, the invention features a method for locating a vascular obstruction. The method comprises determining spectroscopic responses within different regions of a wall of a vessel through an intervening fluid and analyzing spatial fluctuations in the spectral responses in the different regions. Any vascular obstruction is then located to one or more of the regions based on the spatial fluctuations in the spectral responses. 
     In embodiments, the step of determining the spectroscopic responses comprises irradiating the different regions with a near infrared source and detecting diffuse reflectance spectra within the different regions. Also, the step of determining the spectroscopic responses comprises irradiating the different regions with a near infrared source and detecting absorption spectra within the different regions. In the typical example, a catheter is inserted into the vessel, which is irradiated via a head of the catheter. The returning light is detected while rotating the head within the vessels and drawing the head through the vessel to generate a helical raster scan. 
     Preferably, the step of analyzing the spatial fluctuations further comprises determining regions in which the spatial fluctuations of the spectral response exceed a threshold, possibly in a narrowed wavelength band, such as one in which lipids have strong reflectance. 
     In general according to another aspect, the invention features device for locating vascular obstructions. This device comprises an optical catheter that is inserted into a blood vessel and a spectrometer for generating light into and receiving light from the optical catheter to resolve spectral responses of walls of the blood vessel. An analyzer receives the spectral responses and searches for regions of the walls of the blood vessels that exhibit spatial fluctuations in the spectral responses to locate vascular obstructions to the regions based on the spatial fluctuations in the spectral responses. 
     The above and other features of the invention including various novel details of construction and combinations of parts, and other advantages, will now be more particularly described with reference to the accompanying drawings and pointed out in the claims. It will be understood that the particular method and device embodying the invention are shown by way of illustration and not as a limitation of the invention. The principles and features of this invention may be employed in various and numerous embodiments without departing from the scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the accompanying drawings, reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale; emphasis has instead been placed upon illustrating the principles of the invention. Of the drawings: 
         FIGS. 1   a  and  1   b  show a reflectance image and an absorption image, respectively, generated by the near infrared (NIR) scanning of the inside of a blood vessel covering a pullback distance of 0 to 55 millimeters and an angular range of 0 to 360 degrees; 
         FIGS. 2   a  and  2   b  are plots of absorbance as a function of wavelength for various pixels within regions  150  and  154 , respectively, in  FIG. 1   b;    
         FIGS. 3   a  and  3   b  illustrate a device for detecting and analyzing the spectral responses of the vessel walls including detection of thrombus according to the invention; 
         FIG. 4  is a flow diagram showing a method for detecting thrombus according to the present invention; 
         FIGS. 5   a  and  5   b  show a reflectance image and an absorption image, respectively, generated by the near infrared (NIR) scanning of the inside of a blood vessel through flowing blood for another blood vessel; 
         FIGS. 6   a  and  6   b  show a reflectance image and an absorption image, respectively, generated by the near infrared (NIR) scanning of the inside of a blood vessel for stagnant blood for the blood vessel used in the generation of the data in  FIGS. 5   a  and  5   b ; and 
         FIG. 7  is a false color absorption image highlighting potential thrombi. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       FIGS. 1   a  and  1   b  show a reflectance image and an absorption image generated by the near infrared (NIR) scanning of the inside of a blood vessel. These spectral measurements were collected through flowing blood. 
     The guide wire  152  can be seen as a dark shadow across the mean reflectance pullback image in  FIG. 1   a . For this image, an average of the reflectance spectrum across the full wavelength range is taken for each pixel. Thus, each pixel in the image is the average intensity of the reflectance spectrum at that point. 
       FIG. 1   b  is notable because it shows a distinct mottled pattern in regions including region  150  in the peak absorbance image at a pull back distance of approximately 40-55 millimeters corresponding to the location of an obstruction, such as a clot or thrombus. The absorption image is referred to as “peak absorbance” because here the average of each pixel is taken across a limited wavelength range (1200-1240 nm) where lipids have a strong absorbance signal or peak. The average here can be thought of an approximate area under the peak since it is taken after a linear baseline correction. 
       FIGS. 2   a  and  2   b  further characterize the differences between the mottled region  150  at 42-45 millimeters and 275 to 300 degrees in  FIG. 1   b  and the typical spectral characteristics of the vessel walls such as exemplified in pullback region 15-18 millimeters and angle 275 to 300 degrees in  FIG. 1   b . The mottled spectra of the thrombus have significantly different characteristics from the spectra taken from the normal regions. 
     Specifically, the absorbance as a function of wavelength for various pixels within mottled region  150 , for example, is plotted in  FIG. 2   a . It shows a high degree of variation or spectral and spatial fluctuation in the spectral responses. In more detail, each plotted pixel in  FIG. 2   a  exhibits large “intra-pixel” variation in its spectral response over the 1180 to 1260 spectral band that is plotted. That is, each line in  FIG. 2   a  shows large departures from an average response. Moreover,  FIG. 2   a  exhibits a large “inter-pixel” variation in that the spectral responses for the various pixels are very different from each other with a low degree of inter-pixel correlation. 
     The intra-pixel and inter-pixel variation of  FIG. 2   a  is in contrast to pixels of region  154  plotted in  FIG. 2   b . Here the spectral response of each pixel is very smooth, almost linear over the 1180-1260 scan band, a low degree of intra-pixel spectral variation over the scan band. Also the spectral responses of the plotted pixels are very similar to each other, a low degree of inter-pixel variation. Experimentation and observation has shown that these regions of high spatial and high pixel fluctuation in the spectral responses are associated with obstructions, such as thrombi, on the inner walls of the vessel. 
     In one embodiment, the absorbance as a function of wavelength for individual pixels and/or pixels within a region are compared to an average absorbance at each wavelength, and specifically an upper threshold  156  and a lower threshold  158 , which are set based on the calculated average absorbance. When the absorbance of a pixel or pixels within a region repeatedly fall outside these thresholds, the region is said to be mottled and a potential area of a thrombus. 
     In another approach, for detecting inter-pixel variation, a fixed-size rectangular window (pullback position range in millimeters and angular position range in degrees) is sequentially moved along the longitudinal and rotational angle directions of the pullback. At each window position, absorbance spectra corresponding to the locations within the window are averaged to give a single mean absorbance spectrum. An nth order polynomial function is then fitted to the mean absorbance spectrum and the absorbance difference at each wavelength between the measured and fitted spectrum is computed. A score for the window is determined by calculating the root mean square (RMS) of the absorbance differences. The window is then translated by a fixed amount and the scoring process repeated. Scores are thus computed for each window position across the pullback. Regions with high scores are said to be mottled and potential areas of thrombus. 
     In still another approach, for detecting intra-pixel variation, pixels are sequentially selected. For each pixel, nth, such as 1 st  or 2 nd , order polynomial function is fitted to the absorbance spectrum for the pixels and the absorbance difference at each wavelength between the measured and fitted spectrum is computed. A score for the pixel is determined by calculating the root mean square (RMS) of the absorbance differences. Based on a single pixel score or the scores of a group of adjacent pixels, individual pixels or groups of pixels with high scores are said to be mottled and potential areas of thrombus. 
       FIGS. 3   a  and  3   b  illustrate an exemplary device for detecting and analyzing the spectral responses of the vessel walls. 
     The device generally comprises a catheter  56 , a controller  40 , and analyzer  42 . In more detail, the catheter  56  includes the optical fiber bundle. The catheter  56  is typically inserted into the patient  2  via a peripheral vessel, such as the femoral artery  10 . The catheter head  58  is then moved to a desired target area, such as a coronary artery  18  of the heart  16  or the carotid artery  14 . In the embodiment, this is achieved by moving the catheter head  58  up through the aorta  12 . In many cases, the catheter rides on a guide wire that is first advanced through the patient&#39;s blood vessels. 
     When at the desired site, radiation is generated. In the current embodiment optical radiation is generated, preferably by a tunable source  44 , such as a semiconductor tunable laser, and tuned over a range covering one or more spectral bands of interest. In other embodiments, one or more broadband sources are used to access the spectral bands of interest. In either case, the optical signals are coupled into the single mode fibers of the catheter  56  to be transmitted to the catheter head  58 . 
     In the current embodiment, optical radiation in the near infrared (NIR) spectral regions is used for spectroscopy. Exemplary scan bands include 1000 to 1450 nanometers (nm) generally, or 1000 nm to 1350 nm, 1150 nm to 1250 nm, 1175 nm to 1280 nm, and 1190 nm to 1250 nm, more specifically. Other exemplary scan bands include 1660 nm to 1740 nm, and 1630 nm to 1800 nm. 
     However, in other optical implementations, scan bands appropriate for fluorescence and/or Raman spectroscopy are used. In still other implementations, scan bands in the visible or ultraviolet regions are selected. 
     In the current embodiment, the returning light is transmitted back down multimode optical fibers of the catheter  56 . The returning radiation is provided to a detector system  52 , which can comprise one or multiple detectors. 
     A spectrometer controller  60  monitors the response of the detector system  52 , while controlling the source or tunable laser  44  in order to probe the spectral response of a target area, typically on an inner wall of a blood vessel and through the intervening blood or other unwanted signal source, which is typically a fluid, such as a saline flush. 
     As a result, the spectrometer controller  60  is able to collect spectra. When the acquisition of the spectra is complete, the spectrometer controller  60  then provides the data to the analyzer  42 . 
     With reference to  FIG. 3   b , the optical signal of the tunable laser  44  is carried by fiber bundle  102  and directed by the side firing termination  62 , to exit from the catheter head  58  through window  48  and impinge on the target area  22  of the artery wall  24 . The catheter head  58  then collects the light that has been diffusely reflected or refracted (scattered) from the target area  22  and the intervening fluid  108  through window  48  and returns the light in bundle  102  back down the catheter  56  through the multimode fibers to the detector system  52 . 
     In one embodiment, the catheter head  58  spins as illustrated by arrow  110 . This allows the catheter head  58  to scan a complete circumference, 0-360 degrees, of the vessel wall  24 . Also, the head  58  is pulled back in direction of arrow  112 . This combined rotation and longitudinal movement allow a portion or section of the vessel to be analyzed by creating a helical raster scan of the inner vessel walls. Specifically, the movement  110 ,  112  of the catheter head  58  is driven by a pullback and rotation unit  54  that draws the catheter head  58  longitudinally through the vessel such as the coronary or carotid artery, and also drives the catheter head  58  to rotate within that vessel. 
     Generally, the analyzer  42  makes an assessment of the state of the blood vessel walls  24 , which is presented to the operator via interface  70 . The collected spectral response is used to determine whether each region of interest  22  of the blood vessel wall  24  comprises a lipid pool or lipid-rich atheroma, a disrupted plaque, a vulnerable plaque or thin-cap fibroatheroma (TCFA), a fibrotic lesion, a calcific lesion, and/or normal tissue. Each region  22  is also analyzed for the presence of an obstruction, such as thrombosis in the current application. This categorized or even quantified information is provided to an operator via a user interface  70 , or the raw collected spectral images are provided to the operator, who then makes the conclusion as to the state of the region of interest  22 . 
     According to the invention, the analyzer  42  searches for pixels, groups of pixels, or pixels within regions of the vessel walls that exhibit spatial fluctuations in the spectral responses and specifically those regions in which the spatial fluctuations of the spectral response fall outside thresholds  156  and/or  158 . By identifying these regions, the analyzer  42  locates any thrombi or presents the images including the peak absorbance images to the operator, who then finds the spatial fluctuations indicative of thrombi. 
       FIG. 4  is a flow diagram illustrating a process for detecting thrombus in the blood vessels. 
     Specifically, in step  410 , the catheter  56  is inserted into the vessel  14 ,  18  of interest. Then, the pullback and rotation unit  54  drives the catheter head  58  to rotate within the vessel while the head  58  is drawn through the vessel in step  412 . This produces the helical scans and specifically the NIR spectra of the inner walls. 
     Then in step  414 , the helical scans are compiled into images that define regions relative to angular position, i.e., the angular position of the head, and the longitudinal position of the head, during the scan. This produces the images as shown in  FIGS. 1   a  and  1   b.    
     These images are then processed in order to locate any potential thrombus. Specifically, in a first processing step  416 , the spectra are analyzed to remove any artifacts introduced by instrument operation. Specifically, data associated with improper operation of the instrument are removed as being data acquisition errors. 
     Then in step  418 , a dark count estimation and subtraction is performed on the image. Specifically, an estimation of the dark count for each scan is determined and subtracted from the collected spectra. 
     In step  420 , the reflectance and absorbance spectra are generated. These are generated by calculating the ratio of the dark count corrected signal and a reference spectra. 
     The collected spectra are then low pass filtered at a 2 nanometer resolution in step  422 . 
     Also, in step  424 , end regions of the scan, i.e., data generated initially during the pullback and/or near the end of the pullback are excluded at the extremes of the pullback as being outside the area of interest. In one example, only the proximal end of the pullback is excluded in vivo, and even then only if the catheter head was pulled into the guide catheter. Generally, data corresponding to regions outside of the area of interest, e.g. guide catheter, are excluded. 
     Mean reflectance and absorbance peak areas are computed in step  426 . Specifically, for the entire scans, the mean reflectance across the full wavelength region (1180-1260 nanometers) and the area under the base-line corrected absorbance peak between 1200 and 1240 nanometers are calculated. Then, based upon these mean and standard deviation calculations and also possibly averages, the thresholds  156 ,  158  or curve fits are determined and the images are analyzed to find pixels or regions such as region  150  where there are high levels of intra-pixel or spatial fluctuation in the spectral responses in step  428 . These regions are then further analyzed for the existence of a thrombus. 
       FIGS. 5   a  and  5   b  show reflectance and absorption spectra from a pullback through a human coronary artery.  FIG. 5   a  shows the mean reflectance as a function of rotation angle and pullback distance.  FIG. 5   b  shows peak absorbance area (1200-1240 nm) as a function of rotation angle and pullback distance. Spectral measurements are collected through flowing human blood. Thrombus image features are seen at a pullback distance between 34 and 49 millimeters in absorbance image of  FIG. 5   b.    
       FIGS. 6   a  and  6   b  show the reflectance and absorption spectra for the same human coronary artery used to produce  FIGS. 5   a  and  5   b .  FIG. 6   a  shows the mean reflectance as a function of rotation angle and pullback distance.  FIG. 6   b  shows peak absorbance area (1200-1240 nm) as a function of rotation angle and pullback distance. Spectral measurements were collected through stagnant human blood. Thrombus image features are no longer seen at a pullback distance between 34 and 44 mm in absorbance image of  FIG. 6   b . These data suggest that the mottling in the spectral images associated with thrombus area is related to interaction of the obstruction and the flowing blood. The thrombus may act as an obstruction that causes eddies in the flow, thereby altering the NIR scattering properties of the blood. Alternatively, the thrombus may be subject to a fluttering motion by the flow of blood, causing a rapidly varying NIR scattering surface. 
     The analysis shows that the NIR absorbance measured through flowing blood produced a distinctive mottled pattern that correlated with the presence of thrombus in the vessel wall. The pattern was not visible when blood flow through the vessel was stopped, suggesting that the thrombus has a physical effect on light scatter that is detectable. 
       FIG. 7  illustrates one example of an image provided on the display device of the user interface  70 . This is processed absorption spectra in which areas of potential thrombi are identified as described in  FIG. 4 , for example. These regions are then highlighted with false color  710  in order to convey the result of the thrombus detection to the operator. 
     While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.