Abstract:
An apparatus and method to assess the compressibility of blood includes a combination of ultrasound transducers attached to tubing in which blood is flowing. An indicator medium is injected into the bloodstream of the subject over one or more time points and ultrasound waves are transmitted and monitored using transducers and phase lock amplifier to assess transmission time. Using a linear relationship between compressibility and density, changes in blood density are calculated from changes in transmission time to predict blood density changes and then the blood volume and microvascular pooling. This information allows prediction of complications that can occur during hemodialysis or because of post-traumatic fluid replacement and development of therapy to alleviate the complications.

Description:
RELATED U.S. APPLICATIONS 
     This application claims priority to U.S. Provisional Application 60/218,906, filed Jul. 18, 2000. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to systems and methods for non-invasive, continuous monitoring of a patient&#39;s blood density changes in order to determine the blood volume and microvascular pooling of the patient over time. 
     BACKGROUND 
     An apparatus and method are described to monitor the time of sound transmission in the blood stream of a patient and use a linear relationship between compressibility and density for accurate and sensitive assessment of blood density changes due to saline or dialysate dilution. With an appropriate protocol, the density changes are used to determine the blood volume and microvascular pooling of the patient over time. 
     Hypotension and hypovolemia are common circulatory problems that occur during shock (Chien et al,  American Journal of Physiology,  210:1411-1418), traumatic injury, dialysis (Amerling et al in  Clinical Dialysis  3 rd  Edition, Appleton and Lang editors, 1995) and surgical interventions. A variety of disorders and injuries are related to the occurrence of hypotension (Daugirdas,  Kidney International  39:233-246). Fluid losses related to burn injury or hemorrhage due to trauma are examples of situations where compensation for such loss is necessary. Compensation is typically done by infusing isotonic saline, plasma or other physiological solutions into the circulation until arterial pressure is elevated to normal. Although blood volume reduction correlates with reduction in arterial pressure under laboratory simulations of injury and anesthesia, actual occurrences of traumatic blood loss often show only slightly reduced arterial pressures due to the body&#39;s neural compensation mechanisms. Once these mechanisms reach their limits, arterial pressure can drop rapidly. The management of this subnormal arterial pressure is critical to survival; immediate restoration of arterial pressure after traumatic injury can cause more problems than allowing the pressure to remain subnormal. Rapid restoration of arterial pressure results in higher oxygen demand and can dislodge clots that have started to provide homeostasis. 
     While the body&#39;s compensation mechanisms are important to survival, limitations exist in the ability to determine several factors including the volume of blood loss, the distribution of blood volume between the microcirculation and macrocirculation, the necessary volume for infusion, and whether overexpansion of the blood volume has occurred after infusion. Arterial pressure monitoring is unable to provide sufficient information to address these concerns. A need exists for precise monitoring of changes to blood volume and microvascular pooling in patients, particularly over extended time periods. 
     Beyond traumatic injury, a number of medical procedures require such precise monitoring of blood volume. Invasive surgery and dialysis are two common situations where monitoring blood volume changes provide important information related to the outcome of the procedure. For example, 15% to 40% of patients undergoing dialysis in the United States will experience hypotension and, occasionally, circulatory shock. Milder symptoms include muscle cramping and lightheadedness. These dialysis related side effects are implicated in reduced dialysis efficacy. 
     Dialysis and systems for dialysis are well known in the art. These work by extracting a significant fraction of fluid from the circulating blood. Compensation for this reduction in blood volume normally occurs through fluid restituted from the tissue. The activation of the microcirculation by hemodialysis leads to pooling of blood in the microcirculation affecting a low venous return, poor cardiac filling, lowered cardiac output and then hypotension. For patients undergoing a well-controlled fluid removal, these cardiovascular changes, and not hypovolemia, are the reason for hypotension development during the course of hemodialysis. Using saline or dialysate dilution, we can monitor the change in blood volume over regular times, for example every half hour. A continuous change in blood density can be analyzed and microvascular pooling within the circulation can be determined. These parameters can be used by physicians to carefully monitor the cardiovascular changes that are responsible for the development of hypotension in dialysis patients. 
     The use of velocity measurements in blood to assess blood volume has been attempted and described previously. Krivitski, in U.S. Pat. Nos. 5,453,576 and 5,685,989 describes an apparatus and method for measuring several hemodynamic parameters by using a sound velocity sensor. The information contained in the &#39;576 and the &#39;989 patent is incorporated by reference as though cited in its entirety. The technique described uses a linear approximation of a non-linear relationship between the sound velocity and the density of the blood. This approximation introduces additional error into the volume computation, which limits the sensitivity and accuracy of the system. Further, the &#39;576 patent is limited to large variations in sound velocity which make it inaccurate to assess blood volume. 
     The system patented by Schneditz in U.S. Pat. No. 5,830,365 also utilizes sound velocity for the measurement of total protein concentration, and then the blood volume by altering the dialyzer to run at a different ultrafiltrate extraction rate. These two methods are limited to large variations in sound velocity and the requirement of no blood pooling to the microcirculation. 
     Several other devices exist which are used to monitor blood volume or blood parameter changes. These include the Know-Recirc™ hematocrit measurement device produced by H.&amp; H. Control Systems (Jackson, Miss.) and described in U.S. Pat. No. 5,312,550 and an optical device marketed under the Crit-Line® platform and the Transcutaneous Access Flow device by HemaMetrics Corporation (Boston, Mass.) described in U.S. Pat. No. 5,499,627 and 6,117,099. These devices continuously monitor the change in hematocrit over a dialysis session. Increases in hematocrit over the session are interpreted as a decrease in plasma volume thereby theoretically providing a mechanism for monitoring blood volume changes. This method does not account for the Fahraeus effect where microvascular pooling of blood can result in an increase in hematocrit. By not correcting for microvascular pooling, blood volume changes estimated by this device are off by a factor of two or more. Again, sensitivity of this device is limited and can cause incorrect diagnoses or treatments. A similar problem exists in the work of Polaschegg in U.S. Pat. No. 5,230,341. Correction for microvascular pooling and sensitivity are deficient in the &#39;341 patent and incorrect results on the projected blood volume occur leading to potentially harmful treatments. 
     SUMMARY OF THE INVENTION 
     The present invention provides a method and compressibility probe to accurately and reliably determine compressibility and density of blood due to the infusion of saline or dialysate for the quantification of blood volume or microvascular pooling in patients. The invention utilizes blood density changes over time while accounting for the effect of the microcirculation to provide medical professionals with valuable information on microvascular pooling for the prevention of complications related to trauma and hemodialysis. 
     Further, the present invention measures the phase shift between emitting ultrasound and receiving ultrasound, converts the phase shift to transmssion time and subsequently to sound velocity in a corporeal or extracorporeal system, and uses the linear relationship between blood compressibility and density to calculate from sound velocity blood compressibility and blood density. 
     The novel embodiments of the compressibility probe provide significant advantages over the prior art. These include: (1) a better method to determine sound velocity because of the use of higher ultrasound frequency and the procedure for phase shift detection; (2) a better method to determine the density and compressibility of blood by using a precise linear relationship between them instead of an approximation; (3) a new procedure which includes the infusion of isotonic saline and shifting of blood between the circulation and an extracorporeal system; (4) a better interpretation of density changes through either a change in blood volume or through a redistribution of blood volume between the microcirculation and the macrocirculation; and (5) better quantification of microvascular pooling. The combination of these five features enables the compressibility probe to achieve high resolution and to provide crucial information for the physician to select an effective strategy to prevent or treat hypotension in any patient. 
     Blood is a mixture of cells and plasma. The density and compressibility of blood is the sum of its components weighted by the volume fraction. The velocity of ultrasound in blood is related to a variety of factors, including its hematocrit, plasma protein concentration, and total protein concentration. Likewise, blood compressibility also relates to hematocrit, plasma protein concentration, and total protein concentration. These relationships are difficult to identify because of a lack of accurate measurement systems. Attempts at relating variable factors have deduced approximations to be utilized by the system described in the &#39;576 patent and in the Know-Recirc™ and the Crit-Line® hematocrit measurement system. These empirical approximations limit the accuracy and sensitivity of the measurement system and introduce error into the analysis. 
     The more accurate calculation of blood volume and its distribution s taught herein are used to monitor and treat patients more effectively. Software and hardware are configured to generate and receive the ultrasound wave and use the information to monitor the changes to blood volume and redistribution of blood volume in patients. Methods for interfacing the data generated by the compressibility monitoring technique with analytical machinery and additional uses for the compressibility monitoring will become apparent to those of skill in the art based on the description contained herein. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 a  is a schematic drawing of a first embodiment of the compressibility probe; 
     FIG. 1 b  is a schematic drawing of a second embodiment of the compressibility probe for which the transducers have no direct contact with the flowing blood; 
     FIG. 2 is an illustration of the sound waves used to calculate the time shift, the overall transmission time, and subsequently the compressibility and density; and 
     FIG. 3 is a schematic drawing of the compressibility probe as it is used to measure blood compressibility via blood flowing through the tubing of an extracorporeal system. 
     FIG. 4 a  is a top view of one embodiment of the tip of an intravascular probe. 
     FIG. 4 b  is a side view of one embodiment of the tip of an intravascular probe. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The instant invention incorporates a novel linear relationship between compressibility and density to interpret ultrasound velocity measurement. This relationship is not explicitly influenced by hematocrit, plasma protein concentration, blood density or plasma density. The linear relation is supported by the fact that blood is a mixture. As a result, the method improves accuracy of the overall assessment. Processing of ultrasound transducer signals at high frequency is used to assess density and compressibility of the blood. A continuous wave of ultrasound is emitted by an ultrasound transducer excited at an appropriate frequency (f in the range of 10 to 30 MHz). The ultrasound passes through the bloodstream and the tubing. The transmitted ultrasound wave as picked up by the receiving transducer is compared with the emitting wave to determine Time Shift (T shift ), which is the time of the receiving wave shifted from the emitting wave. The value of Time Shift reported is normally within ±0.5 T 0 . The period of ultrasound T 0  is also 1/f. The actual delay in the transmission of this continuous ultrasound contains an integer multiple of the period, n(T 0 ). The overall transmission time is equal to [T shift +n(T 0 )] and is composed of two delays: the transmission time through the fluid domain such as flowing blood or saline, and the transmission time through the tube walls and the delay on the signal transmission through the cables connecting the transducers to the phase shift device and functional generator. Where T 2  is defined to include the tube wall transmission time and the cable delay, L is the distance between the inner walls of the tube and c is the ultrasound velocity of blood, a relationship between these parameters is described in Equation 1. 
     
       
           c=L/[T   shift +( nT   0 )− T   2 ]  Equation 1 
       
     
     When the tube is filled with water or saline (fluids with known ultrasound velocities), a measurement for T shift  provides two measurements to solve for L and [(nT 0 )−T 2 ], thus the ultrasound velocity in blood coming out of any dialysis or vascular technique can be determined by this data processing procedure. 
     The ultrasound velocity and the density in blood (ρ) are related to compressibility (κ) as shown in Equation 2. 
     
       
           κ=ρ/c   2   Equation 2 
       
     
     Tests with ultrasound and the transducer system described herein demonstrate that the compressibility calculated using this relationship is linearly related to the density by a slope (b) and an x-intercept (a) as in Equation 3. 
     
       
           κ=a+bρ   Equation 3 
       
     
     This relationship holds over a wide range of hematocrit, plasma protein concentrations, blood densities and plasma densities. Equation 2 and Equation 3 are combined to accurately solve compressibility and density from the measurement of velocity, allowing a more accurate determination by the density dilution method for determining blood volume than previously described. 
     Density dilution methods are well known methods for blood volume determination. A bolus of isotonic saline at approximately two to three per cent of the total blood volume is infused into the circulation. The saline density is lower than the blood density and mixing of the saline with the circulating blood leads to a reduction in blood density. Where ρ 1  and ρ 2  are the density of the blood prior to and after the infusion of isotonic saline, ρ 3  is the density of saline and ΔV is the increase in total blood volume due to the bolus of saline a novel relationship exists between these densities and the total blood volume (V b ) of the patient. This relationship is shown in Equation 4. 
     
       
           V   b   =A[ΔV (ρ 2 −ρ 3 )/(ρ 1 −ρ 2 )]  Equation 4 
       
     
     The constant A varies slightly by species and accounts for the Faehraeus effect in the microcirculation. The constant A is approximately equal to 1.14 for human and rabbit and can be determined for any animal. The dilution can be repeated over time, for example every hour, to assess the temporal change in blood volume. 
     Over one hour of hemodialysis treatment, one blood volume measurement is carried out at the beginning and another at the end. These two measurements determine the change in blood volume (ΔV b ). In the time between these two measurements, the compressibility probe monitors the blood density and the dialysis machine will report the ultrafiltrate removed from the patient as ΔV dialysis . If the blood density right after the first blood volume measurement is defined as ρ 4  and the blood density before the second blood volume measurement is defined as ρ 5 , the corresponding hematocrits are H 4  and H 5 . Then the pooling of the blood to the microcirculation can be calculated from Equation 5. 
     
       
           ΔV   pooling   =G{V   b (ρ 4 −ρ 5 ) F   cell /(ρ 4 −ρ p )+(Δ V   dialysis −2 ΔV   b )[(1− H   4 )/(1− F   cell   H   4 )](ρ p −ρ 3 )/[3(ρ 4 −ρ p )]−Δ V   b }  Equation 5 
       
     
     Where ρ p  is the density of plasma right after the first blood volume measurement and ρ 3  is the density of the ultrafiltrate or saline, the constant F cell  is 0.87, the constant G is 2.78. The amount of pooling is indicative of how the patient is susceptible to microvascular pooling. 
     Several working models of the cardiac compressibility probe have been developed. FIG. 1 a  depicts one embodiment of the compressibility probe with the ultrasound transducers in direct contact with the blood. A thick walled tube  10  has a pair of ultrasound transducers  16 ,  18  mounted onto the two opposite walls. Fluid, such as blood or plasma, flows along the interior  12  of the tube  10 . In the original signal processing, the transducer  16  is activated by any commercially available pulser/receiver, including a Panametrics 5072PR pulser/receiver, to emit ultrasound impulses of about 15 to 20 Megahertz at a rate of about 100 Hertz. After its transmission through the flowing blood, the second transducer  18  receives the ultrasound signal. The trigger signal from the pulser/receiver triggers a digital oscilloscope such as a LeCroy 9350AL oscilloscope or a Synatec Analog/Digital converter to sample the signal from the receiver  18  at 100 MHz to 1 GHz. Cabling and connectors  20  are shown to connect the transducers  16  and  18  to the electronic devices. The digitized samples so triggered are transferred to a computer for the determination of the transmission time and the calculation of sound velocity using the equations described herein. 
     In FIG. 1 b , a second embodiment of the compressibility probe is described. In this embodiment, the probe exists in a clip  26 , which is mounted with the ultrasound emitting transducer  22  and the receiving transducer  24 . The surfaces of the transducers  22  and  24  are directly in contact with the tubing  14  inserted into the clip  26 . The tubing  14  is connected to an extracorporeal circuit for fluid (blood, plasma or saline) to complete treatment. Cabling and connectors  20  transmit the power from a functional generator or a phase lock amplifier to activate the emitting transducer  22  into producing a continuous wave of ultrasound at a frequency in the range of about 10 to 30 Megahertz. The power signal is used as a reference signal by the phase lock amplifier. The receiving transducer  24  receives the ultrasound wave and sends it to the phase lock amplifier for the determination of its time shift from the reference signal. In this embodiment, the clip  26  has a gap about 5 mm for the insertion of the tubing  14  whose outside diameter is about 6.2 mm. Tubing with a diameter other than 6.2 mm can be used in the system and the dimensioning adjustments to the clip will be obvious to those skilled in the art. Ultrasound gel is used to facilitate the insertion of the tubing  14  into the clip and to provide an airtight contact between the tubing  14  and the transducers  22 ,  24 , preventing errors that can be caused by the reflection of ultrasound through air bubbles. A sensor  28  measures the temperature of flowing blood. The temperature is used to correct the density assessment to the same temperature for the computation of the density change produced by a saline dilution protocol or as the patient responds to treatment. The entire clip-on compressibility probe is housed in an insulator to assure the temperature at the sensor  28  is identical to that of the flowing blood. 
     Using the clip-on compressibility probe, the processing of the transducer signals to assess the transmission time of ultrasound through blood is shown in FIG. 2. A reference signal is generated by the functional generator that is identical to the ultrasound wave  30  generated by the transducer of FIG. 1 b . A second signal is transmitted by the receiving transducer  24  as it receives the ultrasound wave, which has been transmitted through the wall of the tube  14  and blood. The phase lock amplifier determines the time shift T shift  through the mixing of the reference and received signals. For the purpose of illustration, the ultrasound peak  34  is transmitted to become the peak  36 . The overall time delay on ultrasound transmission is the sum of the time shift and a multiple of ultrasound period (nT 0 ). After further correction on signal delay through cables and transducers, the transmission time is processed to determine the sound velocity and then compressibility or density through Equations 1, 2 and 3. 
     The integration of the clip-on compressibility probe with a dialysis system is shown schematically in FIG.  3 . Tubing  14  leads from a blood vessel of a patient to an extracorporeal system  48  such as a dialysis system with a pump, a bubble trap and a hemodialysis filter. In the illustrated embodiment, the blood vessel is an artery  40  of a patient. A portion of the blood  46  flowing through the artery  40  is drawn into the tubing  14  for delivery through the clip-on compressibility probe  26  to the extracorporeal system  48 . Between the compressibility probe  26  and the extracorporeal system  48 , the tubing  14  is connected to a saline bag  36 , which is mounted onto a weighing scale  38 . Normally, a hemostat  32  clamps up the tubing connecting the saline bag to the tubing  14 . For the infusion of saline into the circulation, the hemostat  32  is released and repositioned by clamping the hemostat  34  on the tubing  14  as shown to stop the blood flow coming from vessel  40 . A pump in the extracorporeal system  48  withdraws the saline from the saline bag  36 . When a preset volume of saline is infused as recognized by the weighing scale  38 , the repositioned hemostat  34  is released and returned to its original position  32 . The saline infusion is completed within about one-half minute. The blood  12  eventually is returned to the patient&#39;s circulation through the connection to a blood vessel, such as the illustrated vein  42 . The transducers  22  and  24  in the clip-on probe  26  respectively emits and receives the ultrasound waves which are passed via cabling  20  to the phase lock amplifier  54  for the processing of the ultrasound signals. The processed information is relayed via cabling  56  to the evaluating device  58  where overall transmission time, sound velocity, compressibility and density over the state before and 2-5 minutes after the saline is infused are calculated. The signal from the temperature sensor  28  is also transmitted along this path, through cable  20 , to the phase lock amplifier  54  and then to the evaluating device  58 . Alternatively, the temperature can be transmitted directly from the temperature sensor  28  to the evaluating device  58 . The transmission path of the temperature is dependent upon the final calculations and will be evident to those skilled in the art. Temperature is incorporated in the calculations using the equations described herein. 
     FIGS. 4 a  and  4   b  show a detailed view of the tip of an additional embodiment of an intravascular probe  50  for determining blood compressibility and density. In FIG. 4 a , the tip  52  of the intravascular probe  50  is seen in a bottom facing view. The tip  52  of the intravascular probe  50  takes a generally circular configuration for ease of placement into the blood vessel. In the embodiment illustrated herein the diameter is about 2 mm but this can be adjusted for use in different sized blood vessels or for use in animals. Blood flows between the two arms  54  of the forked probe to the ultrasound transducer and receiver  56  which are mounted on the inside surfaces of the fork arms  54 . The probe arms  54  can be of a flat or beveled configuration. Two or more fiber bundles  58  are mounted on surface between the arms  54  and are used to assess the optical properties of the blood as it passes by the tip  52 . This configuration permits the characterization of, for example, hematocrit and oxygen saturation of the blood, simultaneous with the ultrasound evaluation of density and compressibility. The fiber bundles  58  are constructed to form the shape of a two dimensional cone thereby enabling blood to flow between the fork arms  54  and over the cones  58 . Transmission time of the ultrasound signal is measured as described to determine compressibility of the blood and the information is relayed to the evaluating device to determine density. To determine hematocrit and oxygen saturation, one fiber bundle transmits light to the blood and the other receives the reflected light. 
     A side view of the intravascular probe tip  50  is seen in FIG. 4 b . The ultrasound transducer and receiver  56  are mounted on the inside surfaces of the fork arms  54 . Two or more fiber bundles  58  are mounted on surface between the arms  54  and are used to assess the optical properties of the blood as it passes by the tip. In this view the fork arms are shown with a flat appearance; these may be beveled as well. 
     Additional embodiments of the clip-on compressibility and intravascular probes will become apparent to those of ordinary skill in the art.