Abstract:
A cuvette having a pedestal for transmitting light through a relatively thin layer of blood. While the pedestal enables the use of a small path length it also permits the use of a high volume and/or high flow rate conduit. The pedestal further enables methods of determining various blood parameters in which the path length, d, is fixed; i.e., there are little or no pulsatile variations. Hence, the flow-through cuvette accommodates a large range of blood flow rates without any reduction in accuracy of the hematocrit measurement. The pedestal, because of its elliptical shape, does not damage or hemolyze the individual red blood cells as they pass through. A quantitative method for determining changes in blood volume in view of the path length is provided along with a method for measuring a patient&#39;s cardiac output and oxygen consumption rate. Cardiac output is obtained by injecting a saline arterial bolus and a saline venous bolus into a patient and measuring the change in hematocrit caused by each bolus. The oxygen consumption rate is then determined using the cardiac output and measuring the degree of oxygen saturation. 
     Finally, an improved cuvette and corresponding method of measuring microemboli is provided. The cuvette contains multiple mini-lenses that focus narrow beams of light through the blood. These narrow beams of light are individually monitored by detectors.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This is a divisional of application Ser. No. 08/955,989 filed on Oct. 22, 1997 Now U.S. Pat. No. 6,090,06 which in turn claims priority to U.S. provision applcation Ser. No. 60,029,586, filed Oct. 23, 1996. 
    
    
     BACKGROUND 
     1. Field of the Invention 
     The present invention is directed to an improved extracorporeal conduit and methods and systems for deriving desired biologic constituent concentration values present in a flowing fluid. 
     2. Background 
     Medical professionals routinely desire to know the hematocrit, oxygen saturation, and oxygen consumption rate of a patient. Especially in critically ill patients or in cardiovascular surgery, the oxygen consumption rate, hematocrit value and microemboli content become very significant parameters. 
     The prior art contains disclosures of flow-through cuvettes that may be used in a blood conduit for the spectrophotometric analysis of blood. For example, U.S. Pat. No. 5,456,253 discloses a disposable conduit/cuvette for analyzing blood. 
     OBJECTS OF THE INVENTION 
     It is an object of the present invention to provide systems and methods for noninvasively and continuously monitoring such biologic constituents as the percent blood volume change, hematocrit, oxygen saturation, oxygen consumption rate, and microemboli content during such treatment/procedures as hemodialysis or cardiovascular surgery. 
     It is another object of the present invention to monitor the above mentioned parameters without incurring instabilities, inaccuracies, and the need for recalibration as required in the presently known reflective and transmissive photometric techniques. 
     Another object of the present invention is to measure hematocrit, blood volume, oxygen saturation, oxygen consumption rate, microemboli, and cardiac output and visually display their corresponding values in real-time. 
     It is still another object of the present invention to provide systems and methods that are easy to use, save nursing staff time, and operate noninvasively and economically. 
     Another object of the present invention is to provide a cuvette which may be used in spectrophotometric determinations of desired biologic constituent concentration values of a fluid passing through this cuvette accommodating a large range of flow rates. 
     Another object of the present invention is to provide in this fluid-channeling cuvette a means by which the detection of the above mentioned parameters are unaffected by large variations in flow rates and are likewise unaffected by large variations in oxygen saturation such that the computation of blood constituent and blood flow parameters, including cardiac output, may be easily accomplished. 
     It is a further object of the present invention to provide a flow-through cuvette having a fixed, small path length. 
     These and other objects are achieved by the methods and apparati of the present invention. 
     SUMMARY OF THE INVENTION 
     The present invention provides a cuvette having a pedestal for transmitting light through a relatively thin layer of blood. While the pedestal enables the use of a small path length it also permits the use of a high volume and/or high flow rate conduit. Because the pedestal is situated within a large volume cuvette, the blood pressure within the cuvette remains low. The pedestal further enables methods of determining various blood parameters in which the path length, d, is fixed; i.e., there are little or no pulsatile variations. 
     The ability to change the internal and external dimensions of the blood chamber to accommodate for very large blood flows is important, especially with flow rates of 100 ml/min to 7,000 ml/min used in cardiovascular surgery. Hence, the flow-through cuvette of the present invention accommodates a large range of blood flow rates without any reduction in accuracy of the hematocrit measurement. The pedestal in the cuvette of the present invention because of its elliptical shape does not damage or hemolyze the individual red blood cells as they pass through. 
     The present invention further provides a quantitative method for determining changes in blood volume in view of the path length. 
     The present invention also provides a method for measuring a patient&#39;s cardiac output and oxygen consumption rate. Cardiac output is obtained by injecting a saline arterial bolus and a saline venous bolus into a patient and measuring the change in hematocrit caused by each bolus. The oxygen consumption rate is then determined using the cardiac output and measuring the degree of oxygen saturation. 
     The present invention further provides an improved cuvette and corresponding method of measuring microemboli. The cuvette contains multiple mini-lenses that focus narrow beams of light through the blood. These narrow beams of light are individually monitored by detectors. When a microemboli, such as platelet aggregates, clots, air bubbles, etc. pass through a beam, a “spike” is recorded by a detector. The amplitude and width of spikes provides information on the size of microemboli and the spike frequency provides information on the concentration of microemboli. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 shows a typical hemodialysis tubing circuit and connections. 
     FIG. 2 shows a similar cardiovascular tubing circuit connection with disposable blood chambers in place. 
     FIG. 3 shows a prior art flow-through cuvette. 
     FIG. 4 shows a cross-section of the cuvette of FIG.  3 . 
     FIG. 5 shows a longitudinal cross section of the improved disposable blood conduit with a “pedestal” for effective light piping. 
     FIG. 6 represents a hematocrit dilution curve, due to saline injection. 
     FIGS. 7 a  and  7   b  show two embodiments for the improved disposable blood circuit with a multiple, mini-lensing, linear array. 
     FIG. 8 shows the electronic signal representing the baseline photo-electric noise due to the scattering of photons in a turbid medial such as blood. 
     FIG. 9 is a schematic diagram of the top of the pedestal for the conduit of FIG.  5 . 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In preferred embodiments, measurements are conducted using the apparatus (or modified versions thereof) described in U.S. Pat. Nos. 5,456,253 and 5,372,136, which are incorporated herein as if reproduced in full below. Both of these patents are intended to form part of the present disclosure. It should be understood that the improvements and modifications of the present invention can be applied to a wide variety of blood monitoring apparati and, thus, are not limited to certain preferred embodiments such as the above-cited U.S. patents. 
     FIG. 1 shows a typical hemodialysis tubing circuit and apparati that may be used in the present invention. The numbered components in FIG. 1 are the same as in the corresponding Figure of U.S. Pat. No. 5,456,253. 
     In hemodialysis, blood is taken out of a patient  200  by an intake catheter means, one example of which is shown in FIG. 1 as an input catheter  122 . Input catheter  122  is intravenously inserted into patient  200  at a site  180  and is used for defining a blood passageway upstream of a blood filter used to filter the impurities out of the blood. The blood filter is also called a dialyzer  130 . The unclean blood flows from an artery in patient  200  to a pump means, an example of which is pump  140 . From pump  140 , the blood flows to dialyzer  130 . Dialyzer  130  has an input port  230  and an output port  240 . The pump  140  performs the function of moving the unclean blood from patient  200  into input port  230 , through dialyzer  130 , and out of dialyzer  130  at output port  240 . 
     Specifically, unclean blood in input catheter  122  is transported to input port  230  of dialyzer  130 . After passing through and being cleansed by dialyzer  130 , the blood may receive further processing, such as heparin drip, in hemodialysis related component  300 . The now clean blood is returned to patient  200  after the dialyzing process by means of an output catheter means, an example of which is output catheter  124 . Output catheter  124 , which is also intravenously inserted into patient  200  at site  180 , defines a blood passageway which is downstream from dialyzer  130 , taking the blood output by dialyzer  130  back to patient  200 . 
     As mentioned, the hemodialysis process uses a blood filter or dialyzer  130  to clean the blood of patient  200 . As blood passes through dialyzer  130 , it travels in straw-like tubes (not shown) within dialyzer  130  which serve as membrane passageways for the unclean blood. The straw-like tubes remove poisons and excess fluids through a process of diffusion. An example of excess fluid in unclean blood is water and an example of poisons in unclean blood are blood urea nitrogen (BUN) and potassium. 
     The excess fluids and poisons through an ultrafiltration process are removed by a clean dialysate liquid fluid, which is a solution of chemicals and water. Clean dialysate enters dialyzer  130  at an input tube  210  from a combined controller and tank  170 . The dialysate surrounds the straw-like tubes in dialyzer  130  as the dialysate flows down through dialyzer  130 . The clean dialysate picks up the excess fluids and poisons passing through the straw-like tubes, by diffusion, and then returns the excess fluids and poisons with the dialysate out of dialyzer  130  via an output tube  220 , thus cleansing the blood. Dialysate exiting at output tube  220  after cleansing the blood may be discarded. 
     In some cases, unclean blood flows from an artery in patient  200  to pump  140  and then to dialyzer  130 . Unclean blood flows into dialyzer  130  from input catheter  122  and clean blood flows out of dialyzer  130  via output catheter  124  back to patient  200 . 
     Installed at either end of dialyzer  130  is a spectrophotometry means for defining a blood flow path, for emitting radiation into the blood in the flow path, and for detecting radiation passing through both the blood and the flow path. The spectrophotometry means includes a cuvette means  10  for defining the blood flow path, and an emitter/detector means  100  for emitting and detecting radiation. Within the emitter/detector means is both an emission means for directing radiation and a detector means for detecting radiation. 
     In a prior art embodiment as shown in FIGS. 3 and 4, an example of the emitter/detector means is depicted by the emitter/detector apparatus  100 . An example of the emission means is indicated by a photoemitter  102 . Emitter/detector apparatus  100  also has a detection means, an example of which is depicted as a photodetector  104 . An example of the cuvette means is shown in FIGS. 3 and 4 as cuvette  10 . 
     Emitter/detector apparatus  100  enables the detection by photodetector  104  of the portion of radiation which is directed by photoemitter  102  to cuvette  10  and passes through both the blood therein and cuvette  10 . 
     As shown in FIGS. 1 and 3, a cuvette  10  is installed at either end of dialyzer  130 . Each cuvette  10  has a photoemitter  102  and a photodetector  104  thereon. In the preferred embodiment of the system, photoemitter  102  and photodetector  104  are shown as being held together by a spring loaded C-Clamp type in emitter/detector photo apparatus  100 . 
     The emitter/detector means is electrically connected to a calculation means. In a preferred embodiment of the system, an example of the calculator means is depicted in FIG. 1 as computer  150  which is electrically connected to photoemitter  102  and photodetector  104  on emitter/detector apparatus  100  by means of cable  120  or  128 . 
     Intake catheter  122  takes blood to cuvette  10  situated before input port  230  of dialyzer  130  by input  80 . The blood passes through cuvette  10  and out of output  82  into dialyzer  130 . Emitter/detector apparatus  100  at input port  230  of dialyzer  130  subjects the blood therein to wavelengths of electromagnetic radiation for the purposes of analysis, via spectrophotometry, so that the concentration of a desired biological constituent can be derived. Each photodetector  104 , at both input port  230  and output port  240  of the dialyzer  130 , communicates the detected radiation at least a first and a second wavelength via cable  120  or  128  to computer  150 . 
     Computer  150  calculates both before dialysis and after dialysis concentrations of the sought-after or desired biologic constituent. Computer  150  then displays, respectively, at a first display  152  and a second display  154 , the derived concentration of the biological constituent in either analogue or digital representations. The calculation means, shown here by example as computer  150 , preferably has the multiple capability of simultaneous real-time computation and display of several blood parameters of interest. 
     FIG. 2 shows a similar system that is used during cardiovascular surgery. During cardiovascular surgery the site  181  at which blood is removed and returned is in the groin where the input catheter  122  is connected to the femoral vein and the output catheter  124  is connected to the femoral artery. Also, differing from the dialysis system, the withdrawn blood is oxygenated in an oxygenator  125  that is fed oxygen from oxygenator supply  175  through input tube  210 . 
     A prior art cuvette  10  is shown in FIGS. 3 and 4. The inlet and the outlet to the cuvette are respectively indicated at  16  and  18 , between which lies a cylindrical shaped portion of the cuvette  10 , called herein the conduit. 
     As shown in FIG. 4, there is an upper housing assembly  12  which is assembled into lower housing assembly  8  so as to form cuvette  10 . Upper housing assembly  12  can be installed to lower housing assembly  8  by means of an adhesive. Other and equivalent means such as friction welding or ultrasonic welding can also be employed. The purpose in properly sealing upper housing  12  to lower housing  8  is to create therebetween a fluid impervious and sealed attachment so that fluids conducted through cuvette  10  will not leak, seep, or wick-up at the points of connection between upper housing  12  and lower housing  8 . The lower housing  8  has hand holds or wings  14  by which the cuvette  10  may be manually handled. 
     The conduit incorporates a transducer means. As stated, the transducer means varies the predetermined separation between the two opposed walls with each pressure pulsation in the fluid. In the presently preferred embodiment, an example of the transducer means is represented in FIGS. 3 and 4 as wall  30  which has an opposing wall  32  thereto. 
     The pulsatile flowing fluid flows in the conduit within the area bounded in between a vertical wall  46  and opposed walls  30  and  32 . 
     Inlet  16  and outlet  18  are linearly aligned on either side of the conduit and share a common longitudinal axis passing therebetween. The cylindrical conduit between inlet  16  and outlet  18  has a longitudinal axis passing through opposing walls  30 ,  32  that are normal to the common longitudinal axis of inlet  16  and outlet  18 . As shown in FIG. 4, opposing wall  30  is preferably thinner than opposing wall  32 . 
     The outer surface  37  of opposing wall  32  in the conduit also has a means for receiving an emission means  102  that extends from the wall. The outer surface  35  of the opposed wall  30  has a means for receiving a detector means  104 . In the presently preferred embodiment, the means for receiving a photodetector  104  is indicated in FIGS. 3 and 4 as the combination of the first ring-shaped surface  22  with a second ring-shaped surface  24 , both of which extend from opposing wall  30 . The two ring-shaped surfaces  22  and  24  are styled to accept cylindrical photodetector  104 , shown in FIG.  3 . 
     A means extends from the other one of the opposed walls for receiving a photoemitter means  102 . In the presently preferred embodiment, the ring-shaped surface  26  is concentric to ring-shaped surfaces  22  and  24  and extends from opposing wall  32  so as to accept cylindrical photoemitter  102 . 
     As to the cuvette  10 , it is preferable that ring-shaped surfaces  22  and  24  are concentric to each other and are concentric with ring-shaped surface  26 , and the ring-shaped surface  22  has a lesser inner diameter than ring-shaped surface  24 . 
     The cuvette  10  is described in greater detail in previously incorporated U.S. Pat. No. 5,456,253 at column  8 , line  33  through column  13 , line  30  and FIGS. 2 through 10. 
     The path length d of light through the blood is the distance between the inner surface  33  of separation wall  32  and the inner surface  31  of separation wall  30 . 
     The present invention provides an improvement in the cuvette-conduit system wherein a light-carrying pedestal  92  projects into the blood flow path of the cuvette. An embodiment of the inventive pedestal is illustrated in cross-section in FIG. 5, where like numerals denote like elements to the cuvette of FIGS. 3 and 4. 
     Incorporating a pedestal into a flow through cuvette  10  provides for a shorter path length with little or no pulsatile variation and allows for a large variation in flow rate and a large flow rate without leakage from the cuvette. As the change in path length, Δd, becomes small, ΔI/I becomes small, thus providing more accurate measurements of various blood constituents and blood flow parameters (see, e.g., U.S. Pat. No. 5,372,136). The pedestal of the present invention is a light conduit. The shorter path length created by the pedestal allows more light to reach the detector, especially at strongly absorbed wavelengths such as 660 nm, thus enabling more accurate spectrophotometric determinations. 
     While creating a shorter path length, the pedestal also allows the cuvette to have a large diameter  94  and  96 , i.e., it increases the separation between the inner surface  33  of wall  32  and the inner surface  31  of wall  30 . This decreases pressure inside the cuvette and prevents flow perturbations even when the flow rate is large. 
     Preferably the height H of the pedestal is selected such that the path length Δd through the blood is between about 0.060 and 0.25 inches (0.15 and 0.64 cm) and the distance between walls  30  and  32  is between about 0.27 and 0.35 inches. In a preferred embodiment, the pedestal has a height of approximately 0.165 inches. 
     With reference to FIG. 9, the pedestal is preferably an elliptical cylinder with preferred elliptical measurements of 0.85 inches by 0.200 inches with the long or x-axis  93  of the ellipse parallel to the flow direction  98  and the short or y-axis  95  is transverse to the flow direction. Alternatively, the long axis of the pedestal is preferably about ⅛ the diameter of the interior of the cuvette. The pedestal is preferably made of a rigid material that is transparent to the wavelengths of interest. In a particularly preferred embodiment the pedestal is an elliptical cylindrically-shaped thin, rigid polymeric material formed integrally with separation wall  32 . The ability to place a pedestal, as in FIG. 5, in the midst of a large diameter environment and not be concerned about variations in the blood thickness, d, is an important feature of the present invention. The d dimension cancels out as seen in the following formulae: 
      since:  I   8   =I   o8 ( e   −E     8     d )  (1) 
     
       
           I   8   =I   o8 ( e   −E     13     d )  (2) 
       
     
     
       
         note: log( I/I   o ) 8   =E   8   d   (3) 
       
     
     
       
         log( I/I   o ) 8   =E   13   d   (4) 
       
     
     
       
         and ( I/I   o ) 8 /log( I/I   o ) 13   =E   8   /E   13   (5) 
       
     
     The subscripts 8 and 13 represent wavelengths of 810 nm and 1300 nm, respectively, and E is the extinction coefficient. 
     Thus the hematocrit and blood volume change are noninvasively derived by utilizing this electromagnetic radiation as the information carrier. 
     In a further aspect of the present invention, a technique is provided to measure a patient&#39;s cardiac output. In this technique, two different volumes of saline, for example, 10 ml (arterial—“reference bolus”) and 50 ml (venous—“measuring bolus”), are injected into arterial and venous tubing lines, respectively. As in FIG. 6, the reference bolus may be injected at zero time and the measuring bolus may be injected about 40 seconds later. However, the times of injection are adjustable. By calculating the area under the curves  1  and  2  as seen in FIG.  6  and by knowing the blood flow rate, Q, in the extracorporeal circuit, the cardiac output (C.O.) can be computed as: 
     
       
         C.O.=(50 ml/10 ml)(∫(10 ml bolus)dt/∫(50 ml bolus)dt)Q  (6) 
       
     
     where: Q=blood flow rate of pump and ∫(50 ml bolus) dt=area under curve  2  and ∫(10 ml bolus) dt=area under curve  1 . 
     Once the cardiac output is determined, the oxygen consumption rate can be measured. Assuming the oxygen saturation on the arterial side of the oxygenator to be 100%, measuring the oxygen saturation values on the venous side of the oxygenator, and measuring the hematocrit value and the cardiac output, the instantaneous value for the oxygen consumption rate, dO 2 /dt, is derived as: 
     
       
         dO 2 /dt=(C.O.)(Hct)(13.8/3.0)(S a O 2  -S v O 2 )  (7) 
       
     
     where: C.O.=cardiac output 
     Hct=hematocrit 
     S a O 2  =arterial oxygen saturation=100% 
     S v O 2  =venous oxygen saturation 
     Thus, the present invention also enables the determination of the oxygen consumption rate. 
     The present invention further provides a new apparatus and a new method for the continuous monitoring of the quantity, size, and concentration of microemboli (platelet aggregates, clots, air bubbles, etc.) in the blood. 
     FIG. 7 a  shows the disposable conduit  10  with a multiple, mini-lens, linear array  72 . This mini-lens array method allows for a narrow optical field of view and, hence, aggregate sizing. 
     The mini-lens array is located at the midline  71  which is defined by the cut-line  4 — 4  through FIG.  3 . The midline  71  is transverse to the direction of blood flow. In FIG. 7 a , the direction of blood flow is out of the paper. A group of spaced hemispheric lenses  74  are positioned along the midline  71  on the inner surface  33  of wall  32 . In a preferred embodiment there are 8 lenses, each having a radius of  1  mm. Each lens  74  is spaced 2 mm from the adjacent lens. The two centrally located lenses are each 1 mm from the vertical center line  76 . The mini-lens array acts as a “focusing bubble” on both sides of the disposable detection area, where the LED light source arrays (660 nm, 810 nm, 1300 nm) from the photoemitter  102  are focused by these mini-lenses or “bubbles” onto an array of detectors found in photodetector  104 . By strobing and focusing the LED light sources independently, only a narrow section of the blood conduit is optically viewed with each wavelength individually. Therefore, when a blood embolus (platelet aggregate or clot) passes into that narrow region of illumination, a light transmission difference is sensed and the size of the embolus can be quantified. Noting the background or baseline (normal) scattering characteristics of the blood medium, when clots (or emboli) form, different absorption and scattering values are detected as “spikes.” A digital signal processing algorithm is performed wherein the amplitude of the “spikes” above the baseline are counted as aggregates of a certain diameter (see FIG.  8 ). The number of “spikes” per unit time relate to the concentration (and quantity) and the width of the “spikes” relate to the aggregate sizes. In a preferred embodiment, the mini-lenses may be used in combination with a pedestal. 
     FIG. 7 b  shows an alternative embodiment of the mini-lens array where like reference numerals denote like elements to the mini-lens array in FIG. 7 a . In the embodiment of FIG. 7 b , however, the lenses  74  are located along the inner surface  31  of wall  30 . In this arrangement, the photoemitter  104  shines radiant energy through the blood sample onto the mini-lens array. A series of detectors in the photodetector  104  are associated with each of the lenses  74  to detect presence of an embolus. 
     The described embodiments are to be considered in all respects only as illustrative and not restrictive. The present invention may be embodied in other specific forms without departing from its intent or essential characteristics.