WO2011104710A1

WO2011104710A1 - Device, system and method for in-flow analyte concentration detection

Info

Publication number: WO2011104710A1
Application number: PCT/IL2011/000185
Authority: WO
Inventors: Ilan Paz; Martin Clive Henry Jackson; Stanley Chimes
Original assignee: Flowsense Ltd.
Priority date: 2010-02-23
Filing date: 2011-02-23
Publication date: 2011-09-01
Also published as: EP2538844A1

Abstract

The present invention relates to a device (1200), systems and methods for monitoring analyte concentration in a flowing fluid in real time, and in particular a device, system and method for monitoring urine in real time providing for measuring urinary parameters in real time and over an extended period of time with electrodes (1202) that are disposed essentially perpendicularly relative to the flowing fluid (1211).

Description

DEVICE, SYSTEM AND METHOD FOR IN-FLOW ANALYTE

CONCENTRATION DETECTION

FIELD OF THE INVENTION

The present invention relates to a device, systems and methods for monitoring analyte concentration in a flowing fluid in real time, and in particular a device, system and method for monitoring urine in real time providing for measuring urinary parameters in real time and over an extended period of time. BACKGROUND OF THE INVENTION

Monitoring and detection of analytes for example ion concentration within a flowing fluid is important in a variety of industrial process as well as in the monitoring of bodily fluids for medical applications.

The kidney is an organ which performs several functions in a mammalian body. It receives approximately 20% of the blood flow from cardiac output. The kidney acts as a filter and normally excretes metabolic and foreign waste products in urine at a rate proportional to the blood flow received from the heart. The excretory function serves, inter alia, to maintain fluid and electrolyte homeostasis. Additionally, the kidney has a gluconeogenesis function and also produces hormones and enzymes.

Urine comprises, water, nitrogenous waste, uric acid, electrolytes and other matter. The urinary output rate is typically measured from the bladder. Changes in the urinary output rate may be indicative of one or more conditions including renal failure.

Renal failure may be classified according to the primary kidney structure suffering the injury, the structure normally being one of tubular, insterstitium, vessel and glomerulus. To date, renal failure is diagnosed by performing blood tests, urine analysis, by renal indices and physical examination including scans such as ultrasound, Doppler, computer tomography (CT), magnetic resonance imaging (MRI) and others. However, both blood and urine tests are performed off-line with the results coming at a delay. Such delays may prove to be critical and may significantly reduce the potential for recovery and/or prevent the onset of more serious kidney problems.

Currently known diagnostic methods are dependent on offline testing that do not provide a seamless and sufficiently fine resolution of the tested data, to allow for the identification of such an evolution and/or development of renal failure, for example. Such delays often prove to be critical and may

significantly reduce the potential for discovery of the underlying renal problem.

One urine analyte that is part of standard hospital procedure when performing a urine analysis is the measurement of urine Sodium (Na+) concentration. State of the art procedures for measuring urine sodium concentration requires optimal laboratory conditions and must be performed at regular time intervals. The option of following changes in sodium

concentration at relatively brief intervals for a long period of time in seamless fashion is not provided by state of the art tools for urine Sodium concentration measurements.

SUMMARY OF THE INVENTION

Current urine samples taken for such urine analysis measurement, for example in catheterized patients, do not provide an accurate real time urine analysis results, as the sample is drawn from a urine collection vessel includes urine produced over an extended period of time. Therefore urinalysis results are provided for a mixed fluid of urine production over a given time interval, usually an hour or so and not an instantaneous real time measurement.

Current monitoring method therefore do not provide for the

identification of changes, evolution, trends and/or improvements or degradation of a particular analyte concentration condition in real time and/or over an extended period of time and/or based on an instantaneous urine sample analyzed substantially immediately following urine production. In order to continuously follow changes of analytes in urine production, for example sodium, potassium, pH , one would require a reliable analyte measurement system that may be integrated into an existing urine collection system allowing for measurement and/or monitoring as the urine passes from the body into the collection system.

Accordingly, seamless in-flow sodium concentration is not provided by the state of the art as current methods require that a fluid sample be measured in a laboratory setting requiring electrode to be reconditioned, washed and/or rinsed following every measurement.

Although, US 2006/0100743 to Townsend et al., teaches an automated non-invasive real-time acute renal failure detection system by real-time monitoring of urea and creatnine. The system makes substantially continuous measurements of the urine flow rate and concentration of the analyte of interest. These may be monitored to detect if the patient experiences a delta change in the mass excretion rate of an analyte that is indicative of the onset of acute renal failure or of a change in renal function.

Townsend et al. suggest on page 2 paragraph [0017], that "The absolute concentration of urine analytes are not generally clinically useful because of the large fluctuations in the amount of water dilution from sample to sample and person to person. Because of creatinine's steady excretion rate, it has been used as an internal standard to normalize the water variations."

Contrary to the teachings of Townsend et al, the present invention is directed to systems and methods for detecting body states using continuous urine monitoring of analytes, other than creatinine and urea.

The present invention overcomes the background art by providing, in at least some embodiments, a device systems and methods for detecting body states in relation to urine production and analytes therein, using a continuous, real time urine properties and analyte monitoring for analytes other than creatinine and urea, optionally and most preferably at least one or more of sodium concentration, potassium concentration and pH. The present invention, according to at least some embodiments, relates to device, systems and methods for early detection of body malfunctions in a patient based on real time monitoring of urinary parameters or urine from a catheterized patent that may be indicative of changes of state in the human body.

Within the context of this application the term "reconditioning" refers to a process as is known in the art for refreshing an electrode back to a usable state whereby it is cleaned and recalibrated, and placed in condition for renewed use.

Within the context of this application the term "manifold" refers to a chamber for receiving or distributing a flowing fluid. Most preferably within the context of this application the term refers to a chamber for receiving or distributing a flowing fluid in the form of urine and comprising at least one or more electrodes. Optionally and more preferably the flow rate through the manifold is maintained essentially continuous and at an even streaming flow and/or a flow devoid of turbulence and/or non-turbulent flow. Most preferably the manifold is volume compensated for receiving at least one or more electrodes.

More particularly, the present invention, according to at least some embodiments, relates to a diagnostic method, device, system and apparatus for detecting, in real time, at least one change in a urinary parameter indicative of a body malfunction, for example including but not limited to urinary sodium ion concentration, urinary potassium concentration and urinary pH, any

combination thereof or the like.

Thus according to at least some embodiments of the present invention there is now provided, a diagnostic method and apparatus for detecting at least one change in a urinary parameter indicative of a body malfunction, the method comprising at least semi-continuously monitoring in real time at least one of a sodium level, a potassium level, pH and combinations thereof in the urine of a catheterized patient; whereby at least one parameter is monitored so as to detect one or more changes in the at least one parameter to reflect at least one of a fluid state, an electrolyte balance, a kidney state, a kidney perfusion and an organ perfusion in the patient, indicative of the body malfunction in the patient, in which the monitoring is preferably performed through electrodes that are arranged essentially perpendicularly to the flow of urine through a patient's catheter system, and preferably also in-line to the flow of urine.

The term "semi-continuously" is intended to denote a monitoring at regular intervals of less than once a day, e.g., once every 10-30 minutes or even once every 8 hours, e.g., 3 times a day.

The term "essentially perpendicular" within the context of this application is intended to denote the position and orientation of the electrodes within the manifold and relative to the direction of the flow of the fluid. The orientation of the electrodes relative to the flow is optionally from about 65 degrees up to about 115 degrees, optionally and preferably from about 75 degrees to about 105 degrees, optionally and more preferably from about 80 degrees to about 100 degrees, preferably from about 85-95 degrees, more preferably from about 87 degrees to about 92 degrees and most preferably perpendicular relative to the flow.

Within the context of this application the term electrodes refer to potentiometry electrodes and/or glass membrane electrodes and/or liquid ion- exchanging membrane electrodes (LIX) electrodes or the like. The principle of LEX sensors is the measurements of the electrical potential difference that develops over an ion selective membrane.

In an optional embodiments of the present invention there is provided a diagnostic method as described above for detecting at least one change in a urinary parameter indicative of a body malfunction, the method comprising: a. continuously monitoring and transmitting urine output and urine flow rates of a catheterized patient; b. continuously monitoring in real time at least one of a sodium level, an oxygen level, a potassium level, and combinations thereof in the urine of the catheterized patient; whereby at least one parameter is monitored so as to detect one or more changes in the at least one parameter to reflect at least one of a fluid state, an electrolyte balance, a kidney state, a kidney perfusion and an organ perfusion in the patient, indicative of the body malfunction in the patient.

Measuring and monitoring in-flow analyte properties for example, ion concentration, for example including but not limited to sodium concentration, potassium concentration and pH, any combination thereof or the like may be provided by potentiometry. Potentiometry refers to the determination of an ionic concentration in the tested solution, performed with appropriate electrodes, inferred from the voltage reading of the tested solution where the results are compared to real ionic concentration. The measured voltage is proportional to the Logarithm of the concentration of the analyte. The sensitivity of the electrode is expressed as the electrode Slope - in millivolts per decade of concentration. Thus the electrodes may be calibrated by measuring the voltage in a calibration solutions containing, for example, lOppm and lOOppm of the target ion, and the Slope will be the slope of the calibration line drawn on a graph of mV versus Log concentration, S = [ mV( lOOppm) - mV(lOppm) ] / [Log 100 - Log 10]. Analyte concentration from a sample of an unknown analtye concentration may then be determined by measuring the voltage and plotting the result on the calibration graph to determine the ionic concentration.

An optional embodiment of the present invention provides a device for in-flow measuring and monitoring of at least one or more analyte in a flowing fluid in real time with a plurality of electrodes, comprising:

a manifold including a passageway configured to allow the flowing fluid to flow through the manifold at essentially a continuous and even flow rate; and

wherein the manifold further comprises a plurality of electrode housing for coupling and orienting the electrodes essentially perpendicularly with respect to the flowing fluid flowing through the passageway ;

and wherein the electrode housing further provides for directing a functional portion of the electrode to be in fluid contact with the flowing fluid within the passageway for measuring and monitoring at least one or more analyte in the flowing fluid;

Optionally and preferably the measured flowing fluid is urine.

Optionally and preferably the device may be adapted for coupling with a catheterization urine collection apparatus.

Optionally and most preferably the flow through the manifold passageway may be devoid of turbulence or has a flow that is non-turbulent.

Most preferably the passageway may be provided in the form of a linear conduit comprising a distal end ,medial section, and proximal end wherein the medial section may be volume compensated to provide for the even flow rate across the distal end, medial section and proximal end.

Optionally volume compensation may be configured according to the functional portion of the electrodes.

Optionally the electrodes are oriented at an angle relative to the flowing fluid, the angle selected from the group consisting of: 65-110 degrees, 75-105 degrees, 80-100 degrees; 85-95 degrees, 87 -92 or 90 degree.

Optionally the device may be configured to receive two electrodes. Optionally and preferably, the two electrodes comprise a measuring electrode and a reference electrode. Optionally the electrodes type may be selected from the group consisting of glass membrane electrodes, potentiomery electrodes, or liquid ion-exchanging membrane electrodes, any combination thereof or the like.

Optionally the manifold comprises a holder for securely fixing the device in a fixed position.

Optionally and preferably the device may further comprising a lead in catheter fluidly connected to the proximal end of the passageway; and a lead out catheter fluidly connected to the distal end the passageway. Optionally the connection with the lead in catheter and lead out catheter are mediated with a connector. Optionally and preferably the device may be further coupled with and/or comprise a negative pressure flow tube coupled to the distal end to the passageway.

Optionally the device may be adapted for coupling with a catheterization urine collection apparatus, comprising a urine collection vessel disposed distally to the pressure flow tube; and a urine flow catheter coupled proximally to the passageway proximal end.

Optionally and preferably the measured and monitored analtye may for example include but is not limited to sodium, potassium, pH, or any

combination thereof.

Optionally the analyte measuring and monitoring comprises measuring ionic concentration in the flowing fluid selected from the group consisting of sodium concentration, potassium concentration, pH, or any combination thereof.

Optionally the device of the present invention may further comprise and calibration chamber.

Optionally, the device may comprise, couple or otherwise associate with a sensor selected from the group consisting of color sensor, turbidity sensor and particle size sensor, or any combination thereof.

Optionally measuring and monitoring may be provided for a period of up to 14 days of continuous use without electrode reconditioning or washing.

An optional embodiment of the present invention provides for monitoring apparatus for in-flow monitoring of urine utilizing a catheter for collecting the urine, the apparatus comprising: a catheter tube fluidly connected to the urine collection catheter about its distal portion; an in-flow urine analysis monitoring device fluidly connected to the catheter tube, the monitoring device comprising a receiving connector for fluidly connecting to the catheter tube, and a manifold fluidly connected to the receiving connector, the manifold comprising at least one electrode arranged essentially perpendicularly to a flow of urine through the manifold. Optionally a plurality of electrodes may be arranged essentially perpendicularly to the flow of urine in the manifold.

Optionally the electrodes may be arranged to measure one or more of sodium, potassium, pH or a combination thereof.

Optionally the catheter tube may comprise a negative pressure tube for providing continuous flow of urine through the manifold.

Optionally the apparatus may further comprise a measurement reader for determining a measurement of the one or more of sodium, potassium, pH or a combination thereof. Optionally measurement reader may be coupled or otherwise associated with the in-flow urine analysis monitoring device.

Optionally, the measurement reader further comprises a computational processor for processing the measurement. Optionally the computation processor also processes the measurement according to a calibration reading.

Optionally the apparatus may further comprise at least one detector may be selected from the group consisting of: color detector, turbidity detector, a particle size detector, or any combination thereof. Optionally and preferably the at least one detector selected from the group consisting of: color detector, turbidity detector, a particle size detector, or any combination thereof, may be coupled or otherwise associated with the in-flow urine analysis monitoring device.

An optional embodiment may provide for diagnostic method for detecting at least one change in a urinary parameter indicative of a body malfunction, the method comprising at least semi-continuously monitoring in real time at least one of a sodium level, a potassium level, a pH level and combinations thereof in the urine of a catheterized patient; whereby at least one parameter may be monitored so as to detect one or more changes in the at least one parameter to reflect at least one of a fluid state, an electrolyte balance, a kidney state, a kidney perfusion and an organ perfusion in the patient, indicative of the body malfunction in the patient, in which the monitoring may be preferably performed through electrodes that are arranged essentially perpendicularly to the flow of urine through a patient's catheter system, in line to the system.

An optional embodiment of the present invention provides for a method for in-flow measuring and monitoring of at least one or more analyte in a flowing fluid in real time with a plurality of electrodes, the method comprising: coupling a plurality of electrodes with the analyte measuring device wherein the electrodes are disposed essentially perpendicularly with respect to the flowing fluid; and the electrodes are calibrated relative to a calibration fluid; an d the flowing fluid may be allowed to flow over the functional portion of the electrodes for obtaining measurements and monitoring at least one or more analyte in the flowing fluid in real time.

Optionally the method further comprises communicating the measured analyte in the flowing fluid.

Optionally the monitoring may be continuously provided for up to 14 days without electrode reconditioning or recalibration.

Optionally the calibration may be performed with a calibration kit or by injecting the calibration fluid over the functional portion of the electrodes.

While the invention described herein is presented with respect to a urine analysis measurement such is one application of seamless, in-flow analtye measuring and concentration, for example including but not limited to sodium, potassium, and pH of a flowing fluid in any industrial process. Accordingly embodiments of the present invention may be applied to any flowing fluid, for example pharmaceutical industry, foodstuffs, agriculture or the like.

While the invention will now be described in connection with certain preferred embodiments in the following examples and with reference to the attached figures so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of

formulation procedures as well as of the principles and conceptual aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in order to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the drawings:

Fig. 1A-B are a simplified schematic illustration of a system for continuous monitoring and detection of a change in a body state according to some embodiments of the present invention;

FIG. 2A-C show schematic block diagrams of a system and device according to optional embodiments of the present invention for continuous inflow urine analysis monitoring device; and

FIG. 3 show an urine monitoring device according to a preferred embodiments of the present invention, in which the electrodes are preferably oriented essentially perpendicularly to the flow of urine; and FIG. 4A-B shows optional cross-section view of the urine monitoring device according to preferred embodiment of the present invention as depicted in FIG. 3. FIG. 4A-B shows alternative electrode positioning locations within the urine monitoring device.

FIG. 5 shows a flowchart of an exemplary method according to at least some embodiments of the present invention, featuring in-line flow continuous monitoring of one or more analytes through a plurality of electrodes.

FIG. 6 is a graphical representation of the monitored analyte with the system and method according to optional embodiments of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The principles and operation of the present invention may be better understood with reference to the drawings and the accompanying description.

The following figure reference labels are used throughout the description to refer to similarly functioning parts.

100, 101 continuous monitoring and detection system;

150 analyte monitoring system ;

122 urine collection vessel;

1200 in-flow urine analysis monitoring device;

1202 potentiometry electrodes;

1202a reference electrode;

1202b measuring electrode ;

1206 electrode housing;

1208 manifold ;

1210 catheter connector;

1212 tube connector ;

1214 negative pressure flow tube;

1220 calibration chamber;

1225 potentiometer/pH meter;

1230 manifold holder /coupler Reference is now made to Fig. 1A, which is a simplified schematic illustration of a system 100 for continuous monitoring and detection of a change in a body state according to some embodiments of the present invention, in particular based on inflow urine analysis.

A mammalian patient, such as a human 101, typically has two kidneys

103, 105 and two ureters 107, 109 for transportation of the urine from the kidneys to the bladder 111 and a urethra 113 for passage of the urine from the bladder for excretion out of the body.

System 100 comprises: a) a urine collection apparatus 120; b) a urine flow monitoring apparatus 130; c) a computer system 140; and d) analytes' monitoring system 150.

The urine collection apparatus 120 comprises a catheter 102 suitably connected through the urethra 113 into the bladder 111 , as is known in the art. Apparatus 120 further comprises connection means 108 for connecting between the catheter 102 and a urine collection vessel 122 via urine flow monitoring apparatus 130 or analyzing device 150.

The urine flow monitoring apparatus 130 is typically connected between catheter 102 and connection means 108. Apparatus 130 typically comprises a low flow metering device 106, for example including but not limited to a drop generator and a droplet counter. .

Computer system 140 comprises a display 142, at least one inputting means 144, a memory 146 and a processing device 148.

The analyte monitoring system 150 comprises one or more electrodes and/or sensors 110, 112, 114, 116 for continuously monitoring corresponding one or more analytes. Optionally one or more electrodes may for example be provided in the form of microsensors and/or minisensors and/or macrosensors and/or nanosensors.

Electrodes 1 10, 112, 1 14, 116 are optionally and preferably in communication with computer system 140 for example through wired, wireless, unwired, cellular, Bluetooth, optical, IR, RF or the like connections 124, 126, 128 and 132 or appropriate communication protocol and/or connection.

Optionally, the tips of the microelectrodes may be immersed in the stream of urine in connection means 108, and/or within the urine collection vessel 122.

Optionally individual electrodes may be provided to monitor individual analytes and/or ion and/or properties of the urine sample, for example including but not limited to pH, oxygen, sodium, potassium, or the like.

Optionally, electrode 1 10, may be configured and operative to monitor, for example, a dissolved oxygen concentration, and a dissolved oxygen concentration change in the urine over time.

Optionally electrode 112, may be configured and operative to monitor, for example, a sodium ion concentration, and a sodium ion concentration change in the urine over time.

Optionally electrode 1 14, may be configured and operative to monitor, for example, a potassium ion concentration, and a potassium ion concentration change in the urine over time.

Optionally electrode 116, may be configured and operative to monitor, for example, a pH and a pH change of the urine over time.

Optionally a plurality of varying combinations of different electrodes and other devices for monitoring a large number of parameters of the urine are envisaged to be within the scope of the present invention. For example, the parameters being monitored in the urine may include, but are not limited to, one or more of the following: dissolved oxygen concentration; a dissolved oxygen concentration change over time; sodium ion concentration; a sodium ion concentration change over time; potassium ion concentration; a potassium ion concentration change; pH level; a pH level change over time; a bicarbonate concentration, a change in bicarbonate concentration over time; a carbonate concentration, a change in carbonate concentration over time; an osmolality; a change in osmolarity over time; a carbon dioxide concentration; a change in carbon dioxide concentration over time; a phosphate concentration; a change in phosphate concentration over time.

Figure IB depicts an apparatus 101 according to a preferred

embodiment of the present invention, similar to that depicted in Figure 1 A however characterized in that it comprise a real-time, urine in-flow monitoring device 1200 for analyzing at least one or more urine properties and/or analytes for example including but not limited to Sodium (Na+) concentration,

Potassium (K+) concentration, pH or the like. Optionally monitoring device 1200 may form part of and/ or incorporated and/or coupled with monitoring system 150 described in Figure 1A.

Apparatus 101 preferably comprises a plurality of functional units, as previously described in Figure 1 A, most preferably comprising, urine collection apparatus 120, urine flow monitoring apparatus 130, computer system 140, urine monitoring device 1200 and potentiometer/pH 1225. Optionally urine analyte monitoring device 1200 may form part of and/or integrated with and/or coupled with monitoring system 150, described in Figure 1A.

Optionally and preferably computer system 140 and in-flow urine monitoring device 1200 may be in communication example through wired, wireless, unwired, cellular, Bluetooth, optical, IR, RF or the like connections or appropriate communication protocol and/or connection, as previously described. Optionally communication between device 1200 and computer system 140 is facilitated through electrodes 1202, and or manifold 1208.

Optionally and preferably urine inflow monitoring device 1200 may remain in place over a long-term period for example up to about 14 days , most preferably requiring an initial conditioning and/or calibration of electrodes 1202 and without requiring further washing and/or recalibration and/or reconditioning of electrodes 1202, as will be described in more detail in Figures 2 and 3. Preferably initial calibration of electrodes 1202 is provided with a calibration fluid (not shown) and potentiometer/pH meter 1225.

Optionally apparatus 101 may be provided as a mobile unit within a mobile housing 160. Optionally and preferably mobile housing provides a plurality of compartments for individual functional unit comprising apparatus 101 providing for ease of use.

Apparatus 101 most preferably provides for real time monitoring of urine production and urine properties as urine flows through catheter 102 toward urine collection bag 122 via in-flow urine monitoring device 1200 where most preferably urine analyte and property analysis and/or monitoring is provided. Most preferably urine analysis and monitoring may be provided for at least Sodium (Na+). Optionally urine analysis and monitoring may be provided for at least one or more of Potassium (K+), Sodium (Na+) and pH. Optionally urine analysis and monitoring may be provided for at least two or more of Potassium (K+), Sodium (Na+), pH, and Oxygen. Optionally urine analysis and monitoring may be provided for Potassium (K+), Sodium (Na+), Oxygen and pH.

Figure 2A provides a schematic block diagram of urine analyte device 1200 according to a preferred embodiment of the present invention. Device 1200 is adapt for receiving at least one and more preferably at least two or more electrodes 1202 for sampling, testing and/or monitoring the flowing fluid, most preferably in the form of urine. Device 1200 preferably comprises a manifold 1208 comprising at least one or more electrode housing 1206 and urine sampling/testing passageway 1211. Most preferably electrode housing 1206 provides for orienting and/or placing electrode 1202 in functional and/or operational contact with a flowing fluid flowing through sampling/testing passageway 1211. Most preferably electrode housing 1206 orients electrode 1202 essentially perpendicularly with respect to the flowing fluid flowing through passageway 1211, rendering electrodes 1202 functional and/or operational in monitoring, testing and/or sampling flowing urine.

The orientation of the electrodes 1202 relative to fluid flow through passageway 121 1 is optionally from about 65 degrees up to about 115 degrees, optionally and preferably from about 75 degrees to about 105 degrees, optionally and more preferably from about 80 degrees to about 100 degrees, preferably from about 85-95 degrees, more preferably from about 87 degrees to about 92 degrees and most preferably perpendicular relative to the flow.

Most preferably urine flows from urine flow catheter 102 leading into urine sampling and/or testing passageway 1211, optionally and preferably via connector 1210. Urine flow passageway 1211 is most preferably coupled with and in fluid communication with electrode housing 1206 so as to receive electrodes 1202 such that at least a portion, most preferably the electrode tip and/or membrane, of electrode 1202 is in functional and/or operational contact and may sample, test and/or monitoring the flowing fluid streaming through sampling passageway 1211, most preferably urine. Most preferably following sampling, testing and/or monitoring urine continues to flow through to urine collection vessel 122, optionally via connector 1212 and optionally and preferably through a flow tube 1214 that may be provided in the form of a negative pressure flow tube so as to ensure continued flow from catheter 102 to collection vessel 122 via urine sampling passageway 121 1.

Flow tube 1214 is most preferably utilized with device 1200 and configuration to allow for manifold 1208 wetting so as to ensure that manifold 1208 comprising electrode 1202 stays full so as to not dry out electrodes 1202 in particular the electrode measuring area and/or distal end.

Optionally the catheters are oriented such that the flow rate through catheter 102 and sampling passageway 1211 and collection bag 122 is the essentially same flow rate.

Most preferably the manifold 1208 is fully sealed to protect urine system integrity and prevents leakage.

Most preferably, the electrode housing 1206 provides for aligning electrodes 1202 in line on the tube 1211 through which the urine flows.

Most preferably manifold 1208 is volume compensation most preferably to maintain an even flow rate, avoid turbulence, and/or to avoid pressure differentials within device 1200. Most preferably manifold 1208 may be assembled as part of system 101 and/or 100 in a stable and secure manner to avoid vibrations and movement, optionally with manifold coupler and/or holder 1230.

Optionally manifold 1208 may be controllably orientated within system 101 may be controlled and placed at an angle up or down of up to 25 degrees in gradient, for example with manifold holder and/or coupler 1230. Most preferably regardless of the manifold 1208 orientation electrodes 1202 are maintained in an essentially perpendicular orientation relative to the flow as the electrode orientation is depicted by electrode housing 1206.

Figure 2B shows and optional embodiment of the present invention where a calibration chamber 1220 is integrated, coupled and/or otherwise associated with device 1200 preferably providing for calibrating device 1200 in particular electrodes 1202 prior to first use. Most preferably calibration is preformed while electrodes 1202 are associated with manifold 1208. Most preferably calibration is performed in reference to a calibration fluid (not shown) and potentiometer/pH meter 1225.

Figure 2C depicts a schematic block diagram of an optional embodiment of device 1200, as previously described, that may also optionally feature color detection, particle size detection and cloudiness determination in a flowing fluid, most preferably urine. For example, monitoring device 1200 may optionally and preferably features, couple or otherwise associate with one or more sensors, for example including but not limited color sensor 1250, a turbidity detector 1252, particle size detector 1254, or the like.

Color sensor 1250 may optionally combine photodiodes and color filters integrated color sensors from combine a photodiode, color filter, and trans- impedance amplifier on a single die. The output is then fed to an analog to digital converter ('ADC') for digital processing, for example by a

microprocessor.

Optionally a turbidity detector 1252 may also be included. Turbidity or cloudiness detection may be provided for example by using a dual beam ratio method or a modulated four beam method, with light sensors and emitters around a transparent section of tube at the relevant angles.

Also optionally a particle size detector 1254 may be included. Particle size analysis may be performed for example using optical methods outside a transparent section of pipe using for example light scattering or laser diffraction, such that the light source and detector are placed at relevant positions and angles outside the pipe section.

Optionally a single electrode system could be implemented as for the above (not shown). Also optionally, rather than continuous flow, or in combination with continuous flow, the above measurements are performed with stop/start or discontinuous flow.

Figure 3 provides a perspective view of an optional and preferred illustrative schematic diagram of a preferred embodiment of urine monitoring device 1200 according to a preferred embodiment of the present invention. As previously described most preferably electrodes 1202 are preferably oriented essentially perpendicularly to the flow of urine, rendering them functional, as shown.

Figures 3 and 4 shows an exemplary electrode device 1200 that may be uses with and/or coupled with and/or otherwise coupled with system 101 of Figure IB or with analyte monitoring system 150 of Figure 1 A as part of system 100 for continuously monitoring corresponding one or more analytes in flowing urine.

At least one and more preferably at least two or more electrodes 1202 is used, of which two electrodes 1202 are shown for the purpose of illustration and without wishing to be limiting in any way. Optionally a plurality of electrodes and/or a plurality of electrode pairs may be utilized to measure individual analytes for example including but not limited to sodium, potassium and pH.

In this non-limiting example, electrodes 1202 are arranged for potentiometry, with a reference electrode 1202a and a measuring electrode

1202b for example shown as a glass membrane electrode. Electrodes 1202 are arranged within an electrode housing 1206 to be essentially perpendicular to the flow of urine, flowing through passageway 121 1. Electrode housing 1206 are disposed as part of an enclosed manifold chamber 1208 receiving flowing urine within which sampling, and/or monitoring and/or testing and/or measuring as the urine contacts electrodes 1202.

Urine flows from a catheter connector 1210, through device 1200 via urine sampling/testing passageway 1211, coming into contact with electrodes 1202a,b about their functional distal end, for measurement(s), and then exists through a tube connector 1212 that connects the flow to a urine collection vessel 122 , urine bag or other arrangement. Most preferably and optionally flow through catheter 102 to a urine collection vessel 122 is mediated with a negative pressure flow tube 1214, providing for facilitating continuous flow of urine.

Negative pressure flow tube 1214, for example as described with regard to US Patent Application No. 12/669494, filed on July 16 2008, by at least one of the present inventors and owned in common with the present application, hereby incorporated by reference as if fully set forth herein, for optionally and preferably providing continuous flow of urine.

Optionally negative pressure flow tube 1214 comprises a hydrophobic catheter tube having a diameter of less than six millimeters, the tube being arranged to provide a continuously negative fluid pressure of less than 50 cm equivalent of water therein as a result of a meniscus forming at the beginning of a flow of urine. As a result of the narrowness of the tube 1214 and the repulsion of the urine from the hydrophobic surfaces of the tube 1214 the tube is always full of urine. As a result, a natural negative pressure builds up in the tube 1214 which serves to continuously suction urine. Similarly the orientation of collection bag 212 will contribute to the induction of a negative pressure to allow for continuous urine flow.

Optionally tube 1214 has a diameter of less than five millimeters.

Preferably, the diameter is less than four millimeters. Tube 1214 comprises at least one hydrophobic material preferably selected from a thermoplastic elastomeric material, a thermoplastic material, a curable elastomeric material, a polyamide resin; an elastomer and mixtures or blends thereof.

Tubel214 may be made of the hydrophobic material or internally lined with the hydrophobic material as is known in the art. The material may be selected from, but is not limited to, at least one of polypropylene (PP), polyvinyl chloride (PVC), polyurethane (PU), polyethylene (PE), EVA, latex, and Kraton TM and mixtures or blends thereof.

Negative pressure arises when there is a hydrostatic head due to a flow of urine in the narrow hydrophobic tube 1214 below the vertical level of the urinary catheter 102. This negative pressure exerts a sucking action within catheter 102 and prevents the formation of a bolus of urine while providing continuous urinary flow.

Tube 1214 is disposed to provide a continuously negative fluid pressure of between 5-50 cm water; in some cases between 10-40 cm water; and in other cases, a negative fluid pressure of between 25-40 cm water or the equivalent thereof using a different pressure scale as set forth above.

Figure 4A-B shows a cross section view of device 1200 as previously described showing the internal arrangement of manifold 1208 and the urine sampling/testing passageway 1211. Optionally sampling passageway 1211 is provided in the form of a conduit more preferably, a linear a linear conduit comprising a distal end 121 Id ,medial section 121 lm, and proximal end 121 Id.

Most preferably medial section 1211m may be volume compensated to provide for an even flow rate across the length of passageway 121 1 including distal end

121 Id, medial section 1211m and proximal end 121 lp.

Particularly the orientation of electrode housing 1206 is shown such that electrodes 1202a,b are rendered operation and/or function when disposed essentially perpendicularly to urine flowing through passageway 1211.

Figure 4A-B show alternative electrode positioning locations relative to one another within the urine monitoring device, Figure 4A shows reference electrode 12a first while Figure 4B shows reference electrode 12a second, the device, system and method of the present application function with both optional electrode 1202a,b positioning.

Most preferably urine analysis and monitoring may be provided for at least Sodium (Na+). Optionally urine analysis and monitoring may be provided for at least one or more of Potassium (K+), Sodium (Na+) and pH. Optionally urine analysis and monitoring may be provided for at least two or more of Potassium (K+), Sodium (Na+) and pH. Optionally urine analysis and monitoring may be provided for Potassium (K+), Sodium (Na+) and pH.

Figure 5 shows a flowchart of an exemplary method according to at least some embodiments of the present invention, featuring in-line flow continuous monitoring of one or more analytes through at least one or more preferably two or more or a plurality of electrodes 1202, as described for example with regard to Figures 2-4.

In stage 1, a plurality of electrodes, for example electrodes 1200,a,b, are provided in-line within the flow essentially perpendicularly with respect to the flow , and is connected to the patient's urine catheter system, however preferably without permitting urine to flow past the electrodes. The orientation of the electrodes relative to the flow is optionally from about 65 degrees up to about 115 degrees, optionally and preferably from about 75 degrees to about 105 degrees, optionally and more preferably from about 80 degrees to about 100 degrees, preferably from about 85-95 degrees and most preferably perpendicular relative to the flow.

Next in stage 2, a calibration process is preferably performed before any readings are taken. Calibration may optionally and preferably be performed by using a kit. Optionally a calibration kit comprises a calibration fluid or reference fluid comprising correct quantity of saline fluid which would be injected into the manifold chamber 1208. One or more calibration readings are then preferably performed before commencing urine flow. Optionally, additionally or alternatively, a calibration fluid is injected to the urine flow and the results are determined for calibration. Optionally the manifold 1208 may comprise a dedicated calibration chamber 1220, as shown and described in Figure 2B, comprising a calibration fluid for calibrating electrodes 1202 prior to use. Optionally calibration fluid within calibration chamber 1220 may be replenished and/or replaced following a given number calibrations and/or a threshold urine flow. Optionally calibration fluid may be replenished with the changing of urine flow vessel and/or bag 122.

Next in stage 3 calibration processes is completed by verifying that the expected calibration fluid concentration essentially match the concentration sensed with electrodes 1202. Most preferably calibration of electrodes 1202 is provided relative to the calibration fluid using potentiometer 1225, where the ionic concentration in the calibration fluid is correlated to and/or determined based on voltage reading. Comparison and adjustments are made such that the ionic concentration of the calibration fluid provided with electrodes 1202a,b essentially match the expected concentration of the ionic concentration of the calibration fluid.

Next in stage 4, urine is permitted to flow through the system 101, past the electrodes 1202 and one or more readings are performed.

Finally in stage 5, the ionic concentration of at least one or more analyte in the flow is measured with electrodes 1202. Optionally and preferably results are both measured and provided to a user. Optionally measured concentration results may be stored, displayed and/or otherwise communicated for example including but not limited to at least one or more selected from the group comprising a user, a printout, saved on computer readable media, a processor, a computer, or otherwise communicated to a healthcare provider, user, processor or the like. Optionally measured results may activate an alarm according to a threshold, optionally a threshold may be predetermined or otherwise determined relative t previous concentration readouts.

Thus, the method of the present invention provides an invaluable tool for early detection of abnormal conditions not provided by the standard measuring tools available today. EXAMPLES

Example 1: long term measurement without rinsing with synthetic urine

Although monitoring systems are known for fluids, urine is an unusual fluid in that it is a colloid. As such, regular fluid monitoring systems are not effective, since the materials in the colloid, such as proteins for example, would be expected to foul the electrodes. Other known urine monitoring systems do not teach any particular orientation of the electrodes as being important or useful for monitoring. Without wishing to be limited by a closed list, such art known systems do not feature orientation of the electrodes in an essentially perpendicular manner with regard to the urine flow, nor do they feature the ability to provide continuous flow of urine, for example through negative pressure flow tube 1214.

The above arrangement was tested for one element, namely sodium, to determine whether viable, accurate readings could be determined within a closed chamber, for example manifold 1208. Furthermore, the arrangement was also tested to determine whether the electrodes 1202 could be maintained on line for a reasonable period of time and in use without reconditioning and to observe how the electrode reacted over a period of time to contamination.

A 2L solution of synthetic urine was composed of 1.5 liter d.H20; 36.4 gram urea; 15 gram NaCl; 9 gram KC1; 9.6 gram Na₃P0₄; 4 gram Creatinine; 100 milligram albumin and fill with H20 to complete to 2 Liter solution.

Sodium ion sensor electrodes was calibrated, as described in stages 2 and 3 of Figure 5 with five different solutions to depicted a poteniometric reading providing the system with the ability to correlate and/or convert the measured voltage information, obtained with the test electrode 1202b, relative to the graph therein providing an ionic concentration reading..

Electrodes 1202 were immersed in flowing synthetic urine for 8 days, without rinsing. The urine flow was controlled and provided with a peristaltic, at a rate comparable to the flow that may be experienced by a person. Following a test period of 8 days, the electrodes were removed and the resultant Sodium ion concentrations fluctuation plotted on a graph provided in a graph of Figure 6. Figure 6 shows that inflow sodium ion measurements where the electrodes 1202 were place essentially perpendicularly to the flowing fluid are comparable. The deviation from the gold standard Sodium

concentration measurements showed a negligible deviation. The deviation from the initial measurement wad determined to be about 6mmol/L, well within manufacturer's guidelines for the electrode measurement accuracy.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:

1. A device for in-flow measuring and monitoring of at least one or more analyte in a flowing fluid in real time with a plurality of electrodes (1202), comprising

a. a manifold (1208) including a passageway (1211) configured to allow said flowing fluid to flow through said manifold at essentially a continuous and even flow rate; and

b. wherein said manifold further comprises a plurality of electrode housing (1206) for coupling and orienting said electrodes (1202) essentially perpendicularly with respect to said flowing fluid flowing through said passageway (1211);

c. and wherein said electrode housing further provides for directing a functional portion of said electrode to be in fluid contact with said flowing fluid within said passageway for measuring and monitoring at least one or more analyte in said flowing fluid.

2. The device of claim 1 wherein said flowing fluid is urine.

3. The device of claim 2 wherein said device is adapted for coupling with a catheterization urine collection apparatus.

4. The device of claim 1 wherein the flow through said manifold

passageway is devoid of turbulence or has a flow that is non-turbulent.

5. The device of claim 1 wherein said passageway is a linear conduit

comprising a distal end ,medial section, and proximal end wherein said medial section is volume compensated to provide for said even flow rate across said distal end, medial section and proximal end.

6. The device of claim 5 wherein said volume compensation is configured according to the functional portion of said electrodes.

7. The device of claim 1 wherein said electrodes are oriented at an angle relative to said flowing fluid, the angle selected from the group consisting of: 65-1 10 degrees, 75-105 degrees, 80-100 degrees; 85-95 degrees, 87 -92 or 90 degrees.

8. The device of claim 1 configured to receive two electrodes.

9. The device of claim 8 wherein said two electrodes comprise a measuring electrode and a reference electrode.

10. The device of claim 1 wherein said electrodes are selected from the

group consisting of glass membrane electrodes, potentiomery electrodes, or liquid ion-exchanging membrane electrodes, or any combination thereof.

1 1. The device of claim 1 wherein said manifold comprise a holder for

securely fixing said device in a fixed position.

12. The device of claim 1 further comprising:

a. a lead-in catheter fluidly connected to the proximal end of said passageway ; and

b. a lead-out catheter fluidly connected to the distal end said

passageway.

13. The device of claim 12 further comprising a negative pressure flow tube coupled to the distal end to said passageway.

14. The device of claim 13 wherein said device is adapted for coupling with a catheterization urine collection apparatus, comprising a urine collection vessel disposed distally to said pressure flow tube; and a urine flow catheter coupled proximally to said passageway proximal end.

15. The device of claim 1 wherein said measured and monitored analtye is selected from the group consisting of sodium, potassium, pH, or any combination thereof.

16. The device of claim 15 wherein said analyte measuring and monitoring is provided for measuring ionic concentration in said flowing fluid, selected from the group consisting of sodium concentration, potassium concentration, pH, or any combination thereof.

17. The device of claim 1 further comprising a calibration chamber.

18. The device of claim 1 further comprising a sensor selected from the group consisting of color sensor, turbidity sensor and particle size sensor, or any combination thereof.

19. The device of claim 1 wherein said measuring and monitoring is

provided for a period of up to 14 days without electrode reconditioning or washing.

20. A monitoring apparatus for in-flow monitoring of urine utilizing a

catheter for collecting said urine, the apparatus comprising:

a. a catheter tube fluidly connected to said urine collection catheter about its distal portion;

b. an in-flow urine analysis monitoring device fluidly connected to said catheter tube, said monitoring device comprising a receiving connector for fluidly connecting to said catheter tube, and a manifold fluidly connected to said receiving connector, said manifold comprising at least one electrode arranged essentially perpendicularly to a flow of urine through said manifold.

21. The apparatus of claim 20, comprising a plurality of electrodes arranged essentially perpendicularly to the flow of urine in said manifold.

22. The apparatus of claim 20, comprising a plurality of electrodes arranged essentially perpendicularly relative to the flow of urine in said manifold wherein said electrodes are oriented at an angle relative to said flowing fluid, the angle selected from the group consisting of: 65-110 degrees, 75-105 degrees, 80-100 degrees; 85-95 degrees, 87 -92 or 90 degrees.

23. The apparatus of claim 20, wherein said electrodes are arranged to

measure one or more of sodium, potassium, pH or a combination thereof.

24. The apparatus of claim 23, wherein said catheter tube comprises a

negative pressure flow tube for providing continuous flow of urine through said manifold.

25. The apparatus of claim 24, further comprising a measurement reader for determining a measurement of said one or more of sodium, potassium, pH or a combination thereof.

26. The apparatus of claim 25, wherein said measurement reader further comprises a computational processor for processing said measurement.

27. The apparatus of claim 26, wherein said computation processor also processes said measurement according to a calibration reading.

28. The apparatus of claim 27, wherein said an in-flow urine analysis monitoring device further comprises at least one detector selected from the group consisting of: color detector, turbidity detector, a particle size detector, or any combination thereof.

29. A diagnostic method for detecting at least one change in a urinary

parameter indicative of a body malfunction, the method comprising at least semi-continuously monitoring in real time at least one of a sodium level, a potassium level, a pH level and combinations thereof in the urine of a catheterized patient; whereby at least one parameter is monitored so as to detect one or more changes in the at least one parameter to reflect at least one of a fluid state, an electrolyte balance, a kidney state, a kidney perfusion and an organ perfusion in the patient, indicative of the body malfunction in the patient, in which the monitoring is preferably performed through electrodes that are arranged essentially perpendicularly to the flow of urine through a patient's catheter system, in line to said system.

30. A method for in-flow measuring and monitoring of at least one or more analyte in a flowing fluid in real time with a plurality of electrodes (1202), the method comprising :

a. coupling said a plurality of electrodes with the device of claim 1 wherein said electrodes are disposed essentially perpendicularly with respect to said flowing fluid ; and

b. said electrodes are calibrated relative to a calibration fluid ; c. said flowing fluid is allowed to flow over the functional portion of said electrodes for obtaining measurements and monitoring at least one or more analyte in said flowing fluid in real time.

31. The method of claim 30 further comprising communicating the

measured analyte in said flowing fluid.

32. The method of claim 30 wherein said monitoring is continuously provided for up to 14 days without electrode reconditioning or recalibration.

33. The method of claim 30 wherein said calibration is preformed with a calibration kit or by injecting said calibration fluid over the functional portion of said electrodes.