Abstract:
Described is an apparatus and method of optoacoustic monitoring of blood concentrations of one or more constituents by directing a flow of a patient&#39;s blood through a substantially transparent vessel to optoacoustically detect a concentration of one or more constituents. To detect constituents, pulses of laser light can be passed through the blood flow at one or more frequencies in order to generate an altered laser emission from the exposed blood, and/or induce detectable optoacoustic responses from the constituents. The detectable responses can be detected and measured by analyzing an alteration of the laser emissions and/or the frequency, slope and/or amplitude of the optoacoustic responses for different constituents in the blood.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Application No. 61/450,302 filed Mar. 8, 2011 and incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    The state of a person&#39;s health may be indicated by the constituents and constituent concentrations of the person&#39;s blood. For example, the concentration of various electrolytes including potassium, phosphates, calcium, urea, glucose, etc. are important factors in determining the present state of health as well as indicating the potential for future health problems, their diagnosis and prevention, possibly well before symptoms occur. It may also be desirable to continuously monitor presence and/or concentrations of harmful substances such as drugs, poisons or disease-related components, for example, pathogens, toxins, bacteria, viruses and antibodies, as part of a patient treatment regimen. Although blood sampling and testing are frequently carried out for such purposes, the testing is not continuous but instead is static with the results indicating the constituent concentrations of a single blood draw sample at a time. Moreover, such sampling is not typically repeated frequently during ongoing treatments or during therapy at frequent intervals to determine the real-time or continuous effectiveness of the treatment or therapy. 
       SUMMARY OF THE INVENTION 
       [0003]    The methods and apparatus of the present invention provide a continuous, real-time monitoring and evaluation of a patient&#39;s present and/or progressing health, improvement, or deterioration by monitoring a patient&#39;s blood flow for a selected predetermined period of time. Specific constituents may be identified, selected and monitored such as electrolytes as well as albumin, proteins, poisons, drugs, disease-related components or other identifiable constituents. The method comprises optoacoustic monitoring of a flow of a patient&#39;s blood through a substantially transparent tube, passing pulses of laser light of one or more selected wavelengths through the transparent tube containing the blood flow to induce ultrasonic wave responses from the selected constituents, and detecting and measuring the ultrasonic optoacoustic responses induced from the one or more constituents in response to the laser beam, and/or measuring laser beam amplitude and/or wavelength alteration created by the one or more constituents in response to a laser beam(s). 
         [0004]    An optoacoustic response is induced when a constituent of the effluent absorbs lights from a laser pulse of a certain wavelength, is heated and thermally expands, creating an ultrasonic, photoacoustic (optoacoustic) wave. The wave is monitored by ultrasonic detectors as will be described in more detail hereinafter. The induced optoacoustic response is also measured and the concentration of the constituent(s) determined or calculated from the measured response. 
         [0005]    In one embodiment, the pulses of laser light are directed through the transparent tube through which the patient&#39;s blood flows at one or more frequencies for inducing detectable optoacoustic waves for one or more of the constituents, respectively, and the frequency, slope and/or amplitude of optoacoustic waves generated by the constituents are detected and measured by ultrasound detectors. 
         [0006]    In another embodiment, the method comprises determining laser beam wavelengths that induce optoacoustic detectable responses from selected different constituents, respectively, based on a respective constituent concentration, and determining the concentration of a blood constituent based on the measured optoacoustic wave frequency, slope and/or amplitude. 
         [0007]    In one embodiment, the method comprises detecting and measuring laser beam amplitude change and/or laser beam wavelength alteration or shift for one or more different selected laser beams passing through the constituent containing blood flow, and correlating amplitude change and/or wavelength alteration with corresponding optoacoustic responses and/or constituent concentrations, respectively. 
         [0008]    In one embodiment, a dye, ligand or marker configured to cooperate with one or more of blood constituents is introduced into a blood flow for enhancing optoacoustic responses to laser light pulses. 
         [0009]    In another embodiment, a method comprises determining optimum laser beam wavelengths for generating optoacoustic responses for one or more of the blood constituents, respectively, and directing the optimum laser beam wavelengths into the blood flow containing tube and detecting and measuring the optoacoustic wave frequency, slope and/or amplitude generated by the one or more constituents in response to the respective optimum laser beam wavelengths. 
         [0010]    In one embodiment, the method comprises determining optimum laser beam wavelengths for generating altered laser emissions for one or more of the constituents, respectively, and directing the optimum laser beam wavelength into the blood flow containing tube and detecting and measuring the altered laser emissions generated in response to the optimum laser beam wavelength(s). 
         [0011]    In another embodiment, the method comprises injecting a detectable biologic marker into the patient&#39;s blood upstream of the transparent tube, the marker configured to cooperate with one or more of the constituents for enhancing optoacoustic responses to the laser light pulses. 
         [0012]    In other embodiments, apparatus configured to generate optoacoustic responses for measuring the concentrations of the one or more constituents in a bloodstream utilizing the aforesaid methods are described. Such apparatus includes diagnostic circuits incorporating an optoacoustic monitor, as well as dialysis or therapeutic apheresis systems. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0013]      FIG. 1  is a schematic illustration of a basic blood flow monitoring circuit including an optoacoustic monitoring apparatus; 
           [0014]      FIG. 2  is an enlarged schematic side view illustration of an optoacoustic sensor module of an optoacoustic monitoring apparatus of  FIG. 1  showing laser light and pressure transducer components; 
           [0015]      FIG. 3  is a front view of the optoacoustic sensor module of  FIG. 2 ; 
           [0016]      FIG. 4  is a schematic illustration of a typical chronic dialysis machine with an external stand-alone optoacoustic monitoring apparatus secured adjacent to the machine; 
           [0017]      FIG. 5  is a schematic illustration of a dialysis machine with an integrated optoacoustic monitoring apparatus; 
           [0018]      FIG. 6  illustrates an optoacoustic sensor module of  FIG. 2  mounted on blood flow tubing in a hemofiltration apparatus upstream of a hemofilter; 
           [0019]      FIG. 7A  is a schematic view of a portion of therapeutic apheresis apparatus illustrating use of optoacoustic monitor components; 
           [0020]      FIG. 7B  is a schematic view of a portion of apparatus for patient fluid management incorporating optoacoustic monitor components; and 
           [0021]      FIG. 8  is a schematic illustration of CRRT apparatus illustrating another configuration of locating optoacoustic monitoring components. 
       
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       [0022]    In the following description of apparatus, the same components or devices may be referred to by the same reference numeral in the different drawings. 
         [0023]    In  FIG. 1 , there is illustrated a blood flow monitoring circuit  10  including blood access tubing  51  and blood return tubing  52  configured for directing blood withdrawn from a patient&#39;s vein to a testing apparatus. An optoacoustic monitoring apparatus  30  is positioned along the circuit tubing for monitoring constituents in the blood flow as will be explained further. Blood withdrawn from a patient is directed along circuit tubing  17  using blood pumps  14  and  16 . The blood access and return lines,  51 ,  52 , respectively, are provided with appropriate components such as needles communicating with suitable peripheral veins, for example, needles typically used for blood sampling or IV therapy. Pumps  14  and  16  may be peristaltic pumps such as used for dialysis machines. However, any means for withdrawing the blood from a patient, including tubing and suitable pumps for directing the withdrawn blood to the optoacoustic monitoring components and returning the blood to the patient thereafter in a substantially continuous blood flow, may be used. 
         [0024]    The  FIG. 1  schematic optoacoustic monitoring apparatus  30  configuration comprises a computer  18  cooperating with the optoacoustic sensor  31  including a monitor  19  for displaying results including measurements and concentrations of detected and monitored blood constituents. A suitable computer may also include microprocessors or similar components including software programs configured for calculating constituent concentrations based on optoacoustic measurements of optoacoustic signals including wave frequency, slope and/or amplitude and/or laser beam wavelength alteration or shift detected by the optoacoustic apparatus. A suitable computer may also be provided with software or programs for comparing and correlating the amplitude and/or wavelength shifts with acoustic wave amplitudes. Thus, the optoacoustic monitoring system may be capable of detecting the presence of one or more blood constituents as well as calculating and displaying concentrations of the constituents as the blood flows through the optoacoustic monitoring components. Such monitoring may be accomplished continuously as the blood flows through the system, or intermittently at selected intervals. The apparatus may also be configured to operate the pumps for withdrawing and returning the blood continuously, or at selected intervals. 
         [0025]    In  FIG. 1 , there also is schematically illustrated an embodiment for transmission of processed data signals from the optoacoustic monitor apparatus to a remote location. In the embodiment illustrated, a modem  15  is connected to computer  18  which is connected and communicates with the optoacoustic sensor  31 . The modem provides means for transmission of the processed data signals received from the computer through telephone lines or otherwise transmitted to a modem, display and/or printing equipment at a remote location. Alternatively, wireless transmission may be used, for example where the transmission is through computer connections and/or router to a central processing and/or other monitoring location. Remote transmission of the optoacoustic monitored and processed signals is valuable for giving a physician, technician or other operator real-time and continuing monitoring of the dialysis efficiency as well as detecting and determining adjustments needed to correct and/or maintain patient blood constituents within desired concentration limits and acceptable levels. Such information may be useful in determining and prescribing different treatment therapy as well as modification of dialysis procedures and/or schedules. Such transmission to a remote location may also be used with apparatus embodiments and configurations described hereinafter. 
         [0026]    Referring also to  FIGS. 2 and 3 , the optoacoustic sensor  31  shown in  FIG. 1 , comprises an optoacoustic sensor module  32  including a substantially transparent tube  20  cooperating with a bank of lasers  25  configured for directing pulses of laser light through the transparent tube and blood flowing within the tube. The material for the substantially transparent tube  20  may be any suitable material which will not distort or impede laser light beams, for example, glass, transparent plastic, or other substantially transparent materials through which a blood supply may continuously flow. The term “tube” as used herein is intended to include any vessel or conduit through which blood may be directed. The tube need not be cylindrical but of any suitable shape and size. The tube is also preferably provided with necessary adaptors or fittings for securing the blood supply tubing to and from the sensor module. 
         [0027]    Four lasers, A, B, C and D are shown in the  FIG. 2  configuration. However, other numbers of lasers may be used to meet the apparatus requirements. Examples of lasers which may be suitable include Nd:YAG lasers, Ti:Sapphire, Alexandrite laser, Ruby laser, capable of generating short optical pulses. Another example of a suitable pulsed light source is a compact optical parametric oscillator system which generates pulsed tunable Infrared radiation in wavelength ranges between about 600 nm and about 2440 nm, a pulse duration about 10 ns, and a repetition rate about 20 Hz. An example of a commercially available system is Opolette 532 II (Opotek Inc., Carlsbad, Calif.). Such equipment is further described in U.S. Pat. No. 6,295,160, the description of which is incorporated herein by reference. 
         [0028]    Detection of generated ultrasonic waves generated by blood components in response to the laser light beams may be performed by an ultrasound detector comprising piezoceramic or piezoelectric pressure transducers or optical detectors  26  schematically illustrated in  FIGS. 2 and 3 . An array of such detectors shown is configured opposite the laser light sources, although other configurations may be used. The optoacoustic signals may be amplified and digitized or otherwise generated and modified to be used to calculate and display the desired constituent concentrations. Examples of lasers and an optoacoustic sensing apparatus are described in U.S. Patent Application Publication No. 2008/0255433, the description of which is incorporated herein by reference. Another known optoacoustic apparatus is described in Proc. of SPIE, Vol. 7564, 7564 1H, “Noninvasive Optoacoustic Monitoring Platform,” Esenaliev, et al. © 2010. 
         [0029]    In the apparatus illustrated in the schematic drawings of  FIGS. 1-3 , the number and array of lasers for providing pulsed laser beams, as well as the array of pressure transducers, is shown by illustration only. For example, the four different laser lights may each produce a single different wavelength of light selected to create a desired optoacoustic response. Alternatively, different lasers which may be tuned may be advantageous for scanning the blood flowing through the transparent tube, thereby highlighting the different selected constituents to be monitored. 
         [0030]    Optical detection techniques and apparatus for ultrasound detection may be used in addition to or as an alternative to the piezoceramic or piezoelectric transducer detectors. Examples of such optical ultrasound detectors comprise an optical etalon or Fabry-Perot etalon or interferometer. Another example of an optical sound sensor is a high-bandwidth optical ultrasound sensor described in  J. Biomed Opt.  2011, January-February; 16(1); and Photoacoustic Imaging and Spectroscopy, CRC Press, © 2009 by Taylor &amp; Francis Group LLC. Fabry-Perot etalons are commercially available from LightMachinery, Nepean, Ontario, Canada and more information can be found on the Internet at lightmachinery.com. 
         [0031]    In one embodiment, the optoacoustic monitoring apparatus also includes means for amplifying the detected ultrasonic waves, and, preferably, digitizing the signals. A specific example of a useful amplifier is a low-noise 20-dB preamplifier (Onda Corp., Sunnyvale, Calif.) and a low-noise 40-dB amplifier (Analog Modules Inc., Longwood, Fla.). An example of a useful digitizer is a 100-MHz 8-bit digitizer (NI-5112, National Instruments Corp., Austin, Tex.). 
         [0032]    Referring again to the embodiment shown in  FIG. 1 , the optoacoustic monitoring apparatus computer  18  may include the aforesaid amplifier and digitizer to which the signals are sent from the optoacoustic sensor  31 . Alternatively, the amplifier and/or digitizer may be separate components. As previously described, a suitable computer comprises microprocessor or components provided with software or programs configured for processing the digitalized signals and calculating constituent concentrations based on optoacoustic signals including wave frequency, slope and/or amplitude detected by the sensor  31 . 
         [0033]    As previously described, the apparatus for monitoring concentrations of one or more blood constituents in a continuous stream of blood includes a blood monitoring configuration like that schematically illustrated in  FIG. 1  or may further comprise other blood flow directing equipment, for example, a dialysis machine for carrying out continuous renal replacement therapy (CRRT). In such a circuit, the optoacoustic apparatus may be installed along the blood supply tubing for periodic or continuous monitoring of blood constituents during the dialysis treatment. 
         [0034]      FIG. 4  illustrates the use of a stand-alone optoacoustic monitoring apparatus used with a typical chronic dialysis machine. In the configuration shown, the patient is positioned and “hooked-up” to the dialysis machine  40  for undergoing continuous renal replacement therapy (CRRT). The dialysis machine  40  shown is a machine designed to treat chronic renal disease and is provided with a water feed inlet  41 , dialysis product line  43  and drain line  42 . The patient blood line  46  passes through optoacoustic monitor  44  wherein it is monitored and analyzed as previously described. The blood is then directed into the dialysis machine via blood line  47 , treated, and returned to the patient via return blood tubing line  48 . 
         [0035]      FIG. 5  illustrates a dialysis machine  50  in which the optoacoustic monitoring apparatus  52  is integrated into the dialysis machine. In this embodiment, patient blood access and return lines  56  and  58 , respectively, are connected directly to the dialysis machine. In both embodiments shown in  FIGS. 4 and 5 , the optoacoustic monitoring apparatus comprises sensor components including the sensor module with lasers, transducers, transparent blood flow tube through which the patient&#39;s blood flows as well as the monitor, computer(s), controller(s), and other hardware and software components as previously described. 
         [0036]      FIG. 6  illustrates an embodiment of an optoacoustic sensor monitor  62  installed along blood supply tubing in a CRRT dialysis machine tubing circuit. In the view shown, sensor module  62  is positioned along blood access tubing line  66  upstream from hemofilter  65 . Also shown are effluent line  64 , dialysate line  67  and blood return line  68 . This tubing configuration is also disclosed in U.S. patent application Ser. No. 12/577,513, Publication No. 2010/0089806, and U.S. patent application Ser. No. 12/608,806, Publication No. 2010/0121246, the descriptions of which are incorporated herein in their entireties, respectively. In such a configuration, the monitor screen, and desired hardware and software components, other than the optoacoustic sensor module, may be conveniently positioned outside of the machine for user/operator input, control and observation. 
         [0037]      FIG. 7A  schematically illustrates the use of optoacoustic detection and monitoring apparatus in a therapeutic apheresis system. As previously described, the aforesaid optoacoustic apparatus may be used in detecting and monitoring disease-related blood components, such as poisons, drugs or other harmful substances during therapeutic apheresis. For example, where patient poisoning is to be treated by such apheresis, once the poison is identified, a hemofilter  70  specific for removal of the poison may be selected and installed in the apheresis equipment. The patient&#39;s blood is then directed along the system blood flow circuit through the poison removal hemofilter. In the partial circuit illustrated in  FIG. 7A , two optoacoustic monitoring apparatus  72 ,  74  are shown, installed upstream and downstream, respectively, of the poison removing hemofilter  70 . By comparing the monitored concentrations of poison, efficiency of the poison removal therapy may be continuously monitored in real time. However, a single optoacoustic monitor may be used instead. The aforesaid poison removal is by way of example only, and such a system may be used for any desired or selected apheresis using a hemofilter configured for removal of a specific blood constituent together with one or more optoacoustic monitors. In addition to poison and drug removal, examples of diseases for which such apheresis equipment may also be used to remove pathogenic blood constituents such as listed in Exhibit 1 of U.S. Pat. No. 6,849,183 and Therapeutic Apheresis, Vol. 1, No. 2, 1997. 
         [0038]      FIG. 7B  schematically illustrates a portion of an apparatus circuit for patient fluid management. In such a system, an ultrafilter  75  configured for removing excess fluid from a patient suffering from renal failure. The treatment is referred to as slow continuous ultrafiltration (SCUF) during which the patient&#39;s blood is directed through an ultrafilter which separates and removes plasma water from the blood. In the portion of such a SCUF circuit shown in  FIG. 7B , patient&#39;s blood is directed through ultrafilter  75  and separated plasma water is slowly drained to a fluid collection bag  78  via pump  79 . 
         [0039]    In the apparatus shown in  FIG. 7B , an optoacoustic monitoring apparatus  76 , as previously described, is installed downstream of ultrafilter  75 . The apparatus may be configured to monitor the concentration of an electrolyte such as sodium or potassium in the blood stream being returned to the patient after fluid removal. The optoacoustic monitor apparatus may be configured to calculate the rate of fluid removal based on monitored sodium concentration drop or fluctuation, or determining the loss of other electrolytes, e.g., glucose, amino acids, urea, sodium chloride, from the blood stream. Moreover, a second optoacoustic monitoring apparatus may be used upstream, as shown in  FIG. 7A , and comparison of one or more constituent concentrations before and after ultrafiltration may be useful in monitoring and adjusting fluid removal rates without the need for measuring the volume or the weight of removed patient fluid as is commonly practiced. 
         [0040]      FIG. 8  schematically illustrates an apparatus configured for carrying out continuous renal replacement therapy (CRRT). Such apparatus is further described in U.S. Patent Application Publication No. 2009/0084717, incorporated herein by reference in its entirety. The dialysis apparatus schematically shown comprises an apparatus configured for performing continuous veno-venus hemodiafiltration (CVVHDF). However, other similar dialysis apparatus including systems illustrated in the aforesaid application publication for carrying out continuous ultrafiltration (SCUF), continuous veno-venus hemofiltration (CVVH) and continuous veno-venus hemodialysis (CVVHD) may also be provided with the optoacoustic monitoring apparatus and methods as previously described. Referring to the system and circuit illustrated in  FIGS. 1-3 , and previously described, the optoacoustic methods for detecting and determining the concentration of various important blood constituents may be used in any medical apparatus having extracorporeal access to a patient&#39;s blood flow. The optoacoustic monitoring apparatus may be installed at any one or more desired positions in the circuit. During dialysis or other blood filtration, blood may be monitored prior to and/or after filtration along the therapy circuit. In the illustration of  FIG. 8 , a first optoacoustic monitoring apparatus  82  is shown along the circuit upstream from the hemofilter  80 , and a second optoacoustic monitoring apparatus  84  is provided downstream from the hemofilter, whereby the condition of the blood prior to filtration and after filtration may be compared, thereby giving the physician or operator an analysis of the efficiency of the hemofiltration or dialysis. Alternatively, only one such optoacoustic monitoring apparatus may be used. 
         [0041]    The optoacoustic monitoring apparatus schematically illustrated in  FIGS. 7A ,  7 B and  8  may be integrated with the dialysis machines and comprise optoacoustic sensor modules  32  such as described and shown in  FIGS. 2 and 3  mounted along blood lines in the respective dialysis machines as shown in  FIG. 6  cooperating with a monitor located conveniently elsewhere for observation. Alternatively, the optoacoustic apparatus may comprise stand-alone devices installed along blood lines upstream and/or downstream of a machine as illustrated in  FIG. 4 . 
         [0042]    As previously described, the concentration of blood electrolyte constituents such as sodium, sodium chloride, potassium, phosphates, urea, glucose and/or albumin as well as combinations of two or more of such components may be of particular interest during treatment or in preventative care to determine or confirm a patient&#39;s health. The presence and concentrations of other blood constituents of interest which may be monitored include, by way of example, uric acid, B2 microglobulin and vitamin B12. A more complete list of blood electrolytes as well as other components is disclosed in U.S. Pat. No. 7,481,936, Table 1, incorporated herein by reference. It may also be useful to inject a detectable biologic marker, ligand or fluorescent dye into the patient&#39;s bloodstream upstream of the optoacoustic monitoring equipment. Such a marker or dye is configured to cooperate with the one or more of the constituents for enhancing an optoacoustic response to the laser light pulses. An example of such a dye is indocyanine green (ICG) dye, a chromophere that would be useful in optoacoustic analysis. Any detectable ligand (with or without a chromophore) may be used instead of a “dye” per se. For example, the variable section of monoclonal antibodies could be produced which bind specifically to alpha-microglobulin (or any one of a number of other blood constituents of interest). When introduced into the body, these ligands will bind only to the alpha-microglobulin, and this complex may be detected by altered acoustic responses and/or altered laser responses. Such ligands can also be made with chromophores such as fluorescein, rhodamine, or ICG adding specificity to the technique. 
         [0043]    The optoacoustic constituent detecting and monitoring apparatus and methods may also incorporate methods and apparatus for detecting and measuring laser beam amplitude change and/or laser beam wavelength alteration or shift for one or more selected laser beams passing through a constituent containing blood flow, and correlating the amplitude change and/or wavelength alteration with corresponding constituent concentrations, respectively. Such methods are useful along with or as an alternative to the optoacoustic detectable responses in which the amplitude of acoustic waves from the one or more different ones of the constituents are measured. Where the laser beam amplitude change and/or laser beam wave length alteration or shift is monitored, the optoacoustic apparatus is supplied with appropriate sensors configured for measuring the laser beam amplitude and/or wavelength changes.