Patent Publication Number: US-10779756-B2

Title: Fluid management and patient monitoring system

Description:
This is a Continuation of U.S. patent application Ser. No. 14/118,687, filed Feb. 19, 2014, now U.S. Pat. No. 9,585,605, which is a National Stage Application of PCT/US2012/038598, filed May 18, 2012, which claims priority to the U.S. Provisional Application No. 61/487,937 filed May 19, 2011, which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above disclosed applications. 
    
    
     TECHNICAL FIELD 
     The disclosure relates generally to systems and methods for measuring bioanalytes. More particularly, the present disclosure relates to systems and methods for measuring lactate. 
     BACKGROUND 
     For critical care patients, physicians have long relied on personal examination and clinical laboratory results to determine the presence and concentration of biological analytes in a patient. Clinical laboratories offer a wide range of automated systems for high-volume testing and analytical support in a well controlled, high quality environment. However, clinical laboratories can not provide the immediate results needed to properly treat trauma and multi organ dysfunction/failure patients. 
     To meet the clinical need for immediate test results, several technologies are emerging for testing using reliable, automated analyzers at the patient&#39;s bedside. This type of testing is commonly termed point-of-care (POC) diagnostic testing. POC diagnostic test systems include electrochemical biosensors, optical fluorescence sensors, paramagnetic particles for coagulation test systems, and micromachined devices for both chemical and immunochemical testing. These technologies have allowed multi-analyte chemistry panels to be performed rapidly and have addressed previous obstacles such as calibration of test devices. POC tests can be classified as: 1) in vitro, which is performed at the bedside; 2) ex vivo or para vivo, which is performed at wrist-side; and 3) in vivo, which is performed inside the patient. POC tests offer indirect cost efficiencies and savings such as reduced labor costs, decreased blood identification and transport errors, and reduced patient complications. 
     In vitro or bedside POC devices are used typically in several departments of the hospital including intensive care units; operating rooms; emergency departments (ER); interventional departments; general patient care departments; and outpatient surgery and ambulatory care units. In vitro POC diagnostic tests offer a wide range of diagnostic tests, similar to the clinical laboratory. In vitro POC diagnostic test systems typically are not connected on-line to the patient and require an operator for blood sampling. Key categories of diagnostic test in the POC diagnostic market include arterial blood gases, blood chemistries, blood glucose, coagulation, drugs-of-abuse testing, hemoglobin, hematocrit, infectious diseases, and therapeutic drug monitoring. Other categories include cancer markers, cardiac markers, cholesterol detection, immunodiagnostics, infectious disease detection, lactate, and thrombolytic monitoring. 
     Ex vivo POC diagnostics use external sensors for on-line real-time testing with little to no blood loss. Typically, sampled blood flows through a closed system to minimize blood contact. Ex vivo POC systems minimize problems associated with in vivo sensors, including clotting, inaccuracy, calibration drift, and an inability to recalibrate once in the patient. U.S. Pat. No. 5,505,828 discloses an exemplary ex vivo POC system. 
     In vivo POC diagnostics offer considerable potential in the treatment of most critical and unstable patients. Although many companies are developing in vivo sensors, technical hurdles have thus far kept in vivo sensors from common commercial use. 
     Ex vivo and in vivo POC diagnostics, since they are on-line systems, can reduce quality control and information integration errors that occur with clinical or in vitro POC tests. Quality control errors are commonly due to operator errors, not instrument errors or device failures. Exemplary errors include inappropriate specimen volume, inaccurate calibration, use of deteriorated test strips, inadequate validation, insufficient instrument maintenance, bad timing of the test procedure, and use of the wrong materials. Clinical information system integration allows test data collected at the bedside to be put directly into the patient record. This improves the efficiency of the patient management process, allowing the integration of the laboratory&#39;s information system and clinical information systems, providing a “seamless” flow of all types of patient information. 
     Although there exists a number of viable systems for determining blood lactate values, no current commercially available device can economically monitor patient trend lactate valued in near real time over a desired period of eight hours. This requirement is considered important to further ongoing research that increasingly suggests trend lactate monitoring will emerge as an important clinical standard in the critical care setting. 
     SUMMARY 
     The present disclosure relates generally to systems and methods for measuring bioanalytes. More particularly, the present disclosure relates to systems and methods for measuring lactate. 
     One aspect of the present disclosure relates to a fluid management system consisting of a pumping mechanism, a check valve, a reservoir, tubing, a sensor, and connective means for enabling either ex vivo or in vivo lactate monitoring by a clinician. This arrangement composes a disposable set assembly that is mounted by a clinician to a lactate monitor that in turn provides the data acquisition, storage and display functions. The disposable set assembly is designed for low cost injection molding and low volume, partially automated assembly by means of ultrasonic or laser welding. Sub-assemblies of the set may be fabricated using transfer adhesive films or U.V. curable epoxies. 
     Another aspect of the present disclosure relates to the pump device, which includes a housing defining a piston chamber (or cylinder) and a piston is reciprocally mounted within the chamber. The reciprocating motion of the piston results in a reciprocating flow of fluid within a single fluid line. The reciprocating flow provides a first cycle calibration and anticoagulant wash when caused to move a volume toward the patient as a result of a “push” direction of the piston, and wherein the directional control of fluid is by a “valve-less” means that uses the differential pressure gradient of two possible inlet ports accessing the piston cylinder. A second cycle in the opposite or “pull” direction causes a patient blood sample to be drawn over the sensor arrangement, where the blood analysis is taken, and wherein a check valve provides the directional control of the fluid. 
     A further aspect of the present disclosure relates to the calibrant as being a common infusion agent such as Ringers Lactate, and the anticoagulant being such as sodium citrate. 
     A further aspect of the present disclosure relates to a method of relating the fluid line component volumes with the sensor position, whereby the “pull” stroke of the piston in traversing the cylinder provides a complete volume needed to acquire a substantially pure sample of the patient blood and locate it over a working electrode of the sensor. Likewise, the “push” stroke of the piston in traversing the cylinder provides a complete volume needed to wash the analyzed blood components from the fluid line and position a substantially pure anticoagulant/calibrant mixture over the working electrode of the sensor. Importantly, the “push” stroke results in a volume of fluid moved that is greater than the “pull” stroke by an amount equal to the portion of the piston cylinder traversed that is located above the check valve. By controlling that portion of the cylinder length, an amount of fluid may be determined that is sufficient to flush the fluid system completely by pushing a defined quantity of anticoagulant/calibrant into the patient. Once defined and incorporated into the mechanism the possible volume that may be introduced is a novel, self-limiting feature, that prevents the patient from over or under infusion of the anticoagulant/calibrant mixture in the flush cycle. This feature eliminates positioning variability and chain of potential failure modes inherent in typical analogous systems using pumping mechanism drivers and software as the actuating mechanisms. 
     The system is so designed as to have inherent safety features, simplified set up, intuitive patient interface, and minimal total parts required for manufacture. Additional design goals are to reduce both cost and potential failure modes and to facilitate sterilization and packaging. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a schematic depiction of an embodiment of an ex vivo sensor system or arrangement constructed in accordance with the principles of the present disclosure; 
         FIG. 1B  is a schematic depiction of an embodiment of an in vivo sensor system or arrangement constructed in accordance with the principles of the present disclosure; 
         FIG. 2  is a perspective view of an example pump module suitable for use in the sensor systems of  FIGS. 1A and 1B  constructed in accordance with the principles of the present disclosure; 
         FIG. 3  is a schematic depiction of the pump module of  FIG. 2 ; 
         FIG. 4  is a perspective view of a portion of the pump module of  FIG. 2  with a piston exploded from the bottom housing of the pump module; 
         FIG. 5  is a flow routing diagram showing a calibration fluid flow path between a reservoir and a pump body during a second cycle of the pump module duty cycle; 
         FIG. 6  is a schematic depiction of a sectional view of an example check valve of the pump module with the sectional view taken between an upper housing and a lower housings looking toward the upper cylinder passage of the pump body; 
         FIG. 7  is a schematic depiction of an embodiment of an air vent plug. 
         FIG. 8  is a schematic depiction of one example embodiment of an ex-vivo planar sensor suitable for use in the sensor system of  FIG. 1A ; 
         FIG. 9  is a schematic depiction of an embodiment of a fluid connector portion of the ex-vivo planar sensor of  FIG. 8 ; 
         FIG. 10  is a schematic depiction of an embodiment of an electrical connector skin mount portion of the ex-vivo planar sensor of  FIG. 8 ; 
         FIG. 11  is a schematic depiction of one example embodiment of an in-vivo planar sensor suitable for use in the sensor system of  FIG. 1B ; 
         FIGS. 12 and 13  are schematic depictions of a longitudinal cross-section of the in-vivo sensor of  FIG. 11 . 
     
    
    
     DETAILED DESCRIPTION 
     Reference will now be made in detail to exemplary aspects of the present disclosure which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. 
     An aspect of the present disclosure relates to systems and methods for providing on-line monitoring/measurement of bioanalytes in a patient. One particular aspect of the present disclosure relates to systems and methods for providing on-line measurement of lactate concentrations in a patient. 
     Lactate is a small molecule that is produced by all tissues and organs of a patient&#39;s body that are in “distress”. When the demands for oxygen exceed the supply at a location in a patient&#39;s body, then a state of low perfusion exists and lactate is produced at the location. For example, lactate is produced if a patient is bleeding, if a patient&#39;s heart is failing, if a person&#39;s limb is in danger of being lost, or if a person is not getting enough oxygen to breathe. Thus, many life and limb threatening clinical states produce elevated blood lactate levels, even in the face of adequate oxygen delivery to the patient. It is a matter of oxygen supply and metabolic demand. 
     At the cellular level, lactate is inversely proportional to the vital cellular energy stores of adenosine triphosphate and is produced within six seconds of inadequate perfusion or cellular injury. It is thus an ideal biochemical monitor of cellular viability at the tissue level, and of patient viability at the systemic level. 
     Clinically, the dire significance of elevated and rising blood lactate values is known. Trauma physicians and clinical evidence support the hypothesis that a simple, inexpensive, continuous, monitor of lactate in the trauma setting will save lives by providing timely, life-saving information that will help dictate triage and therapy. For example, an emergency room patient who has a blood lactate level of 4 mM has a 92% mortality rate within the next 24 hours. If this level is 6 mM, then the mortality rate rises to 98%. In animal experiments, blood lactate levels begin to rise within minutes of hemorrhage, and conversely, begin to fall just as quickly with adequate resuscitation. In multivariate analysis, blood lactate is the best indicator of the degree of shock (superior to blood pressure, heart rate, urine output, base deficit, blood gas and Swan-Ganz data) and is proportional to the shed blood volume. Blood lactate levels correlate with a trauma patient&#39;s chances of survival. Therapy that fails to control a patient&#39;s increasing lactate levels must be modified or additional diagnoses quickly sought. 
       FIG. 1A  illustrates an example sensor system or arrangement  210  that is one example implementation of the present disclosure. The sensor system  210  generally includes a catheter  212  for withdrawing a test fluid sample, a sensor module  214  for measuring an analyte such as lactate in the sample, and a pump module  216  for controlling the fluid flow within the sensor system  210 . In the example shown, the sensor module  214  is an ex vivo analyte sensor  214  for the on-line measurement of bioanalytes, such as lactate, glucose or other analytes. 
     Certain types of sensor modules  214  include an electrochemical sensor  234 . In some implementations, the electrochemical sensor  234  of the sensor arrangement  210  is a sensor fiber for detecting or measuring bioanalytes. In other implementations, the electrochemical sensor  234  of the sensor arrangement  210  includes a plate sensor or other suitable sensor. Additional information pertaining to ex vivo sensors 214 can be found in U.S. Pat. No. 6,117,290, the disclosure of which is hereby incorporated herein by reference. In other implementations, the electrochemical sensor of the sensor arrangement  214 ′ includes one or more sensor fibers for detecting or measuring bioanalytes. 
     To promote manufacturing and operational efficiency, certain implementations of the system  210  have a single uninterrupted flow path  218  adapted to extend from a patient  217 , past an analyte sensor  214 , to a pump module  216 . The phrase “single uninterrupted flow path” is intended to mean that the system  210  does not use flow control devices to selectively provide and inhibit access between the pump module  216  and the patient  217 . The flow path  218  is formed by a first flow line  220  extending between the catheter  212  and the sensor module  214 , a test chamber  222  formed through the sensor module  214 , and a second flow line  223  extending between the sensor module  214  and the pump module  216 . 
     The pump module  216  includes a pump body  215  and a source of calibration fluid (a reservoir)  235 . The pump body  215  and reservoir  235  are integral as described in more detail herein. The pump module  216  functions as a source of calibration fluid with respect to the single uninterrupted flow path  218  that extends between the pump module  216  and the catheter  212 . The pump module  216  draws calibration fluid from the calibration fluid reservoir  235  through a flow line  236 . In certain implementations, a check valve sub-assembly  201  is located at the flow line  236  to inhibit contamination of the calibration fluid in the reservoir  235 . 
     Calibration fluid contained by the reservoir  235  includes a predetermined concentration of a calibrant. Some example calibrants include lactate for lactate sensors and glucose for glucose sensors. The calibration fluid can include a variety of other components in addition to a calibrant. For example, the calibrant fluid may contain an anticoagulant, such as sodium citrate. One example calibration fluid includes a solution of sodium citrate, saline, and lactate. Of course, lactate may be used as a calibrant if a lactate sensor is being used in the system. Other types of calibrant that may be used with other types of sensors include glucose, potassium, sodium, calcium, and ringers lactate. 
     The example system  210  is preferably a bi-directional system. The term “bidirectional” is intended to mean that fluid flow is directed back and forth across the sensor  214  through the single flow line  218 . While certain implementations of the system  210  could utilize valves between the pump module  216  and the patient  217 , the bi-directional nature of the system  210  eliminates the need for such internal valves along the continuous flow path. The bi-directional nature of the system  210  also reduces manufacturing costs. This cost reduction is particularly significant in disposable systems. 
     In operation, the pump module  216  can direct fluid flow in a first direction from the pump module  216  toward the patient  217 . In particular, the pump module  216  directs calibration fluid from the pump module  216  past the sensor  214  at towards the patient  217 . This fluid flow allows the sensor  214  to be calibrated and the entire flow path to be coated with anticoagulant. After calibration of the sensor  214  and coating of the flow path with anticoagulant, the pump module  216  reverses the flow in the system  210  to cause a fluid sample to flow from the patient  217  across the sensor  214  toward the pump module  216 . This fluid flow allows an analyte level of the fluid sample to be measured by the sensor  214 . 
     The reservoir  235  of the pump module  216  defines a first port and a second port. A fill septum  202  at the first port enables filling of the reservoir  235  with the anticoagulant/calibrant fluid mixture during manufacture. In certain implementations, a silicone rubber fill septum  202  may be located at the first port to enable ingress of calibration fluid without the need for a complex valve mechanism. An air vent  203  at the second port allows air to be displaced from a void within the reservoir  235  as the calibration fluid is added during manufacture. The air vent  203  also allows air to enter the reservoir  235  as the calibration fluid is depleted during the normal operation of the device. In certain implementations, a non-woven Teflon® vent  203  may be located at the second port to enable ingress/egress of ambient air into the reservoir  235 . 
     The sensor system  210  also includes a control unit or controller  224  that operates the pump module  216 . In certain implementations, the control unit  224  interfaces with a pump driver  226 , the sensor  214  (via a connector  251 ), an input unit  227  (e.g., a keyboard), memory  229 , and a display unit  230  (e.g., a monitor). It will be appreciated that the control unit  224  can include any type of controller, such as a micro-controller, a mechanical controller, an electrical controller, a hardware-driven controller, a firmware-driven controller, or a software-driven controller. Similarly, the pumping mechanism driver  226 , display unit  230 , and the input unit  227  can include off-the-shelf components. For example, a suitable device incorporating a controller, a display unit, an input unit, and a pumping mechanism driver is sold by Alaris Corporation of San Diego, Calif. under the name Ivac®, or by Medex Corporation of Hilliard, Ohio under the name MedFusion®. 
     In some implementations, the first and second flow lines  220 ,  223  are formed by conventional medical tubing. In certain embodiments, the first and second flow lines  220 ,  223  have relatively small diameters that inhibit mixing between fluid samples drawn through the catheter  212  and calibration fluid dispensed into the flow path  218  through the pump module  216 . Mixing also is inhibited because the dynamic frontier formed between the fluid sample and the calibration fluid has a small area so that contamination by diffusion is minimized. Additionally, mixing is also inhibited by maintaining laminar flow within the flow path  218 . 
     In certain embodiments, the flow lines  220  and  223  have inner diameters less than about ⅛ inches. In certain embodiments, the flow lines  220  and  223  have inner diameters less than about 0.1 inches. In certain embodiments, the flow lines  220  and  223  have inner diameters of about 0.010 inches. In certain embodiments, the flow lines  220  and  223  have inner diameters of between about 0.002 inches to about 0.015 inches. In certain embodiments, the flow lines  220  and  223  have inner diameters of between about 0.005 inches to about 0.010 inches. In another example implementation, the flow lines  220  and  223  have inner diameters of about 0.005 inches. In one example implementation, the flow lines  220  and  223  have inner diameters of about 0.006 inches. In another example implementation, the flow lines  220  and  223  have inner diameters of about 0.007 inches. In another example implementation, the flow lines  220  and  223  have inner diameters of about 0.008 inches. In another example implementation, the flow lines  220  and  223  have inner diameters of about 0.009 inches. 
     In accordance with some aspects, a diameter D 1  of the second flow line  223  is less than a diameter D 2  of a flow line  236  leading to the check-valve  201 . In some implementations, the diameter D 1  of the second flow line  223  is significantly less than the diameter D 2  of the flow line  236  to the check-valve  201 . When the pump body  215  is creating fluid flow in the second direction, the pump body  215  is applying a suction pressure at the check valve  201  and at the second flow line  223 . However, due to the difference in diameters D 1 , D 2 , the calibration fluid enters the pump body  215  from the reservoir  235  instead of the fluid from the second flow line  223 . 
     In some implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is at least 1.5 times the size of the diameter D 1  of the second flow line  223 . In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about twice the size of the diameter D 1  of the second flow line  223 . In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about three times the size of the diameter D 1  of the second flow line  223 . In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about four times the size of the diameter D 1  of the second flow line  223 . In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about five times the size of the diameter D 1  of the second flow line  223 . 
     In some implementations, the diameter D 2  of the check-valve passage  236  is at least 0.01 inches. Indeed, in some implementations, the diameter D 2  is at least 0.02 inches. In certain implementations, the diameter D 2  is about 0.025 inches. In certain implementations, the diameter D 2  is between about 0.03 inches and about 0.06 inches. In certain implementations, the diameter D 2  is about 0.03 inches. In certain implementations, the diameter D 2  is about 0.04 inches. In certain implementations, the diameter D 2  is about 0.05 inches. In certain implementations, the diameter D 2  is about 0.06 inches. In other implementations, the diameter D 2  may be larger than 0.06 inches. 
     In accordance with some aspects, a transverse cross-sectional area of the second flow line  223  is less than a transverse cross-sectional area of the passage through the check-valve  201  between the reservoir  235  and the pump body  215 . In some implementations, the transverse cross-sectional area of the second flow line  223  is significantly less than the transverse cross-sectional area of the check-valve  201 . When the pump body  215  is creating fluid flow in the second direction, the pump body  215  is applying a suction pressure at the check valve  201  and at the second flow line  223 . However, due to the difference in transverse cross-sectional areas, the calibration fluid enters the pump body  215  from the reservoir  235  instead of the fluid from the second flow line  223 . 
     In some implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is at least twice the size of the transverse cross-sectional area of the second flow line  223 . In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about three times the size of the transverse cross-sectional area of the second flow line  223 . In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about five times the size of the transverse cross-sectional area of the second flow line  223 . In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about ten times the size of the transverse cross-sectional area of the second flow line  223 . In other implementations, the transverse cross-sectional area of the flow passage  236  sufficiently larger than the transverse cross-sectional area of the second flow line  223  to produce flow at only the flow passage  236  when suction is applied to both. 
     In accordance with some aspects, the port for the check valve subassembly  201  divides the pump body  215  into a first volume V 1  and a second volume V 2 . The first volume V 1  refers to the internal volume of the pump body  215  between the check valve port and a liquid interface surface of a piston  219  when the piston  219  is located at a lower-most point within the pump body  215 . The second volume V 2  refers to the internal volume of the pump body  215  between the check valve port and the liquid interface surface of the piston  219  when the piston  219  is located at an upper-most point within the pump body  215 . 
     When a piston  219  of the pump body  215  is located in the first volume V 1 , the piston  219  blocks the flow line  236  to the reservoir  235 . Accordingly, movement of a piston  219  within the first volume V 1  of the pump body  215  towards the second volume V 2  does not apply a suction pressure to the reservoir flow line  236 . Rather, such a movement of the piston  219  applies a suction pressure to the second flow line  223 , thereby causing a fluid sample to be withdrawn from the patient  217 . Continued movement of the piston  219  into the second volume V 2  of the pump body  215  unblocks the reservoir flow line  236 . As noted above, the difference in size between the check valve port and the second flow line  223  causes the continued movement of the piston  219  to pull calibration fluid into the pump body  215  from the reservoir  235  instead of continuing to pull the fluid sample from the patient  217 . Moving the piston  219  back towards the first volume V 1  pushes the calibration fluid from the pump body  215  into the second flow line  223  towards the sensor  214 . The calibration fluid pushes the fluid sample from the sensor  214  back towards the patient  217 . 
     The calibration fluid mixes with the withdrawn fluid sample to a limited extent at a region where the two fluids meet. Fresh calibration fluid from the reservoir  4  mixes with spent calibration fluid to a limited extent at a region where the two fluids meet. As noted above, the dimensions of the flow lines  220 ,  223  inhibit mixing of fluids. Accordingly, any mixing occurs over a limited length of the flow line  220 ,  223  known as a diffusion barrier. The length over which such barriers extend will depend on the concentration of the fluids, the duty cycle of the pump module  216 , the size of the flow lines  220 ,  223 , as well as other factors. A first diffusion barrier DB 1  refers to a length beyond which the blood sample cannot diffuse into the calibration fluid. A second diffusion barrier DB 2  refers to a length beyond which fresh calibration fluid cannot diffuse into the spent calibration fluid. 
     In some implementations, the pump module  216  initiates a duty cycle of the sensor system  210  by washing the sensor  214  and flow lines  223 ,  220  in calibration fluid. In some implementations, the pump module  216  first moves in a “pull” direction through the second volume V 2  of the pump body  215  to draw fresh calibration fluid into the pump body  215 . In other implementations, the pump module  216  previously drew in fresh calibration fluid at the end of the previous duty cycle. The pump module  216  moves in a “push” direction to expel the calibration fluid. In some implementations, the pump module  216  expels sufficient calibration fluid to coat at least the first flow line  223  and the test chamber  222  of the sensor  214 . In certain implementations, the pump module  216  expels sufficient calibration fluid to also coat at least part of the first flow line  220 . In one implementation, the pump module  216  expels sufficient calibration fluid to coat the entire first flow line  220 . After calibrating the sensor  214 , the pump module  216  moves in the “pull” direction draws a blood sample from the patient towards the sensor  214  for analysis. 
     When the piston  219  of the pump module  216  moves in the “push” direction towards the lower-most point within the pump body  215 , the piston  219  pushes the fresh calibration fluid from the pump body  215  into the second flow line  223 . In some implementations, the second volume V 2  of the pump body  215  is at least as large as a total volume of the second flow line  223  and the test chamber  222 . In certain implementations, the second volume V 2  of the pump body  215  is at least as large as the total volume of the second flow line  223 , the test chamber  222 , and the second diffusion barrier DB 2 . In such implementations, the pump  216  will expel sufficient fresh calibration fluid to wash these areas so that spent calibrant will not interfere with the sensor readings during calibration. In one implementation, the second volume V 2  of the pump body  215  is as large as the total volume of the second flow line  223 , the test chamber  222 , and the first flow line  220 . In such implementations, the pump module  216  expels sufficient fresh calibration fluid to purge all spent calibrant from the flow line and into the patient. 
     When the piston  219  of the pump module  216  moves along the first volume V 1  of the pump body  215  in the “pull” direction, the piston  219  draws a blood sample from the patient  217  into the first flow line  220 . In some implementations, the first volume V 1  of the pump body  215  is at least as large as a total volume of the first flow line  220  and the test chamber  222 . In certain implementations, the first volume V 1  of the pump body  215  is at least as large as a total volume of the first flow line  220 , the sensor test chamber  222 , and the first diffusion barrier DB 1 . In such implementations, the pump  216  will pull a sufficient volume of blood to flush the sensor test chamber  222  of calibrant before analyzing the blood sample, thereby enhancing the accuracy of the test analysis. As noted above, continued movement of the piston  219  through the second volume V 2  in the “pull” direction causes the second volume V 2  of the pump body  215  to fill with fresh calibration fluid. 
     To minimize patient discomfort, another aspect of the disclosure relates to using relatively low flow rates through the flow path. In some implementations, the catheter  212  is a relatively small diameter catheter capable of withdrawing blood samples from a capillary bed of a patient  217 . In certain implementations, the catheter  212  is capable of withdrawing blood or other fluid samples at a rate less than 100 microliters per minute. Indeed, in certain implementations, the catheter  212  is capable of withdrawing blood or other fluid samples at a rate less than 50 microliters per minute. Such low flow rates enable sample fluids to be drawn from low flow regions, such as capillary beds, thereby further reducing patient discomfort. Of course, conventional venous catheters and other types of catheters also can be utilized for withdrawing test fluids from a patient. In other implementations, other techniques for withdrawing fluid samples from a patient in medical applications (e.g., intracranial pressure (ICP), microdialysis and iontophoresis) also may be utilized. 
     The general system  210  described above provides a simple and relatively inexpensive system for monitoring analyte levels, such as lactate levels, in a patient. Because the system  210  has a minimal number of parts, the system is suited for disposability. The simplicity of the system  210  also facilitates assembly and operation of the system. 
       FIG. 1B  illustrates another example sensor system or arrangement  210 ′ providing an in vivo analyte sensor for the on-line measurement of bioanalytes, such as lactate, glucose or other analytes. The sensor system  210 ′ generally includes a catheter  212  for withdrawing a test fluid sample, an in vivo sensor module  214 ′ for measuring an analyte, and a pump module  216  for controlling the fluid flow within the sensor system  210 . In the example shown, the example sensor arrangement  210 ′ includes the same or similar pump module  216  as the sensor system  210  of  FIG. 1A . In other implementations, other types of pumps may be utilized. In the example shown, the sensor arrangement  210 ′ also includes the control unit or controller  224  that operates the pump module  216 , the pump driver  226 , the input unit  227  (e.g., a keyboard), the memory  229 , and the display unit  230  (e.g., a monitor) of the sensor system  210  of  FIG. 1A . 
     The sensor  214 ′ includes an electrochemical sensor. Additional information pertaining to in vivo sensors  214 ′ can be found in U.S. Publication No. 2010/0252430 to Say et al., the disclosure of which is hereby incorporated herein by reference. In some implementations, the electrochemical sensor of the sensor arrangement  214 ′ includes one or more sensor fibers for detecting or measuring bioanalytes. In one example implementation, the sensor fiber includes a composite sensor fiber having a dielectric core, a conductive layer, and a sensing layer. 
     Some example sensor fibers are described in U.S. Pat. Nos. 5,264,105; 5,356,786; 5,262,035; and 5,320,725, the disclosures of which are incorporated by reference herein. Further examples of sensor fibers are described in U.S. application Ser. Nos. 13/129,325, filed May 13, 2011, and titled “Electrochemical Sensor Module,” the disclosure of which is incorporated by reference herein. Other examples of sensor fibers are described in PCT Publication Nos. WO 2009/032760, and WO 2009/051901, the disclosures of which are incorporated by reference herein. In other implementations, the electrochemical sensor of the sensor arrangement  214 ′ may include a plate sensor or other suitable sensor. 
     To promote manufacturing and operational efficiency, certain implementations of the system  210 ′ have a single uninterrupted flow path  218 ′ adapted to extend from a patient  217 , past the in vivo analyte sensor  214 ′, to a pump module  216 . The phrase “single uninterrupted flow path” is intended to mean that the system  210 ′ does not use flow control devices to selectively provide and inhibit access between the pump module  216  and the patient  217 . The flow path  218 ′ is formed by a first flow line  220 ′ extending between the patient  217  and the sensor module  214 ′, a test chamber  222  formed in the sensor module  214 ′, and a second flow line  223  extending between the sensor module  214 ′ and the pump module  216 . The pump module  216  functions as a source of calibration fluid with respect to the single uninterrupted flow path  218 ′ that extends between the pump module  216  and the patient  217 . 
     As noted above, calibration fluid contained by the reservoir  235  of the pump module  216  includes a predetermined concentration of a calibrant. Some example calibrants include lactate for lactate sensors and glucose for glucose sensors. The calibration fluid can include a variety of other components in addition to a calibrant. For example, the calibrant fluid may contain an anticoagulant, such as sodium citrate. One example calibration fluid includes a solution of sodium citrate, saline, and lactate. Of course, lactate may be used as a calibrant if a lactate sensor is being used in the system. Other types of calibrant that may be used with other types of sensors include glucose, potassium, sodium, calcium, and ringers lactate. 
     The example system  210 ′ is preferably a bi-directional system. The term “bidirectional” is intended to mean that fluid flow is directed back and forth across the in vivo sensor  214 ′ through the single flow line  218 ′. While certain implementations of the system  210 ′ could utilize valves between the pump module  216  and the patient  217 , the bi-directional nature of the system  210 ′ eliminates the need for such internal valves along the continuous flow path. The bi-directional nature of the system  210 ′ also reduces manufacturing costs. This cost reduction is particularly significant in disposable systems. 
     In operation, the pump module  216  can direct fluid flow in a first direction from the pump module  216  toward the patient  217 . In particular, the pump module  216  directs calibration fluid from the pump module  216  past the in vivo sensor  214 ′ at towards the patient  217 . This fluid flow allows the sensor  214 ′ to be calibrated and the entire flow path to be coated with anticoagulant. After calibration of the sensor  214 ′ and coating of the flow path with anticoagulant, the pump module  216  reverses the flow in the system  210  to cause a fluid sample to flow from the patient  217  across the sensor  214 ′ toward the pump module  216 . This fluid flow allows an analyte level of the fluid sample to be measured by the sensor  214 ′. 
     In some implementations, the first and second flow lines  220 ′,  223 ′ are formed by conventional medical tubing. In certain embodiments, the first and second flow lines  220 ′,  223 ′ have relatively small diameters that inhibit mixing between fluid samples and calibration fluid dispensed into the flow path  218 ′ through the pump module  216 . Mixing also is inhibited because the dynamic frontier formed between the fluid sample and the calibration fluid has a small area so that contamination by diffusion is minimized. Additionally, mixing is also inhibited by maintaining laminar flow within the flow path  218 ′. 
     In some implementations, the first flow line  220 ′ has a relatively small diameter catheter capable of withdrawing blood samples from a capillary bed of a patient  217 . In other implementations, the first flow line  220 ′ has a larger diameter. In certain embodiments, the second flow line  223 ′ has an inner diameter less than about ⅛ inches. In certain embodiments, the second flow line  223 ′ has an inner diameter less than about 0.1 inches. In certain embodiments, the second flow line  223 ′ has an inner diameter of about 0.010 inches. In certain embodiments, the second flow line  223 ′ has an inner diameter of between about 0.002 inches to about 0.015 inches. In certain embodiments, the second flow line  223 ′ has an inner diameter of between about 0.005 inches to about 0.010 inches. In another example implementation, the second flow line  223 ′ has an inner diameter of about 0.005 inches. In one example implementation, the second flow line  223 ′ has an inner diameter of about 0.006 inches. In another example implementation, the second flow line  223 ′ has an inner diameter of about 0.007 inches. In another example implementation, the second flow line  223 ′ has an inner diameter of about 0.008 inches. In another example implementation, the second flow line  223 ′ has an inner diameter of about 0.009 inches. 
     In accordance with some aspects, a diameter D 1 ′ of the second flow line  223 ′ is less than a diameter D 2  of a flow line  236  leading to the check-valve  201  of the pump module  216 . In some implementations, the diameter D 1 ′ of the second flow line  223 ′ is significantly less than the diameter D 2  of the flow line  236 ′ to the check-valve  201 . As disclosed above, when the pump body  215  is creating fluid flow in the second direction, the pump body  215  is applying a suction pressure at the check valve  201  and at the second flow line  223 ′. However, due to the difference in diameters D 1 ′, D 2 , the calibration fluid enters the pump body  215  from the reservoir  235  instead of the fluid from the second flow line  223 ′. 
     In some implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is at least twice the size of the diameter D 1 ′ of the second flow line  223 ′. In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about three times the size of the diameter D 1 ′ of the second flow line  223 ′. In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about four times the size of the diameter D 1 ′ of the second flow line  223 ′. In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about five times the size of the diameter D 1 ′ of the second flow line  223 ′. In certain implementations, the diameter D 2  of the flow passage  236  to the check-valve  201  is about six times the size of the diameter D 1 ′ of the second flow line  223 ′. In other implementations, the diameter D 2  may be about ten times the diameter D 1 ′. 
     In some implementations, the diameter D 2  of the check-valve passage  236  is at least 0.01 inches. Indeed, in some implementations, the diameter D 2  is at least 0.02 inches. In certain implementations, the diameter D 2  is about 0.025 inches. In certain implementations, the diameter D 2  is between about 0.03 inches and about 0.06 inches. In certain implementations, the diameter D 2  is about 0.03 inches. In certain implementations, the diameter D 2  is about 0.04 inches. In certain implementations, the diameter D 2  is about 0.05 inches. In certain implementations, the diameter D 2  is about 0.06 inches. In other implementations, the diameter D 2  may be larger than 0.06 inches. 
     In accordance with some aspects, a transverse cross-sectional area of the second flow line  223 ′ is less than a transverse cross-sectional area of the passage through the check-valve  201  between the reservoir  235  and the pump body  215 . In some implementations, the transverse cross-sectional area of the second flow line  223 ′ is significantly less than the transverse cross-sectional area of the check-valve  201 . When the pump body  215  is creating fluid flow in the second direction, the pump body  215  is applying a suction pressure at the check valve  201  and at the second flow line  223 ′. However, due to the difference in transverse cross-sectional areas, the calibration fluid enters the pump body  215  from the reservoir  235  instead of the fluid from the second flow line  223 ′. 
     In some implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is at least twice the size of the transverse cross-sectional area of the second flow line  223 ′. In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about three times the size of the transverse cross-sectional area of the second flow line  223 ′. In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about four times the size of the transverse cross-sectional area of the second flow line  223 ′. In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about five times the size of the transverse cross-sectional area of the second flow line  223 ′. In certain implementations, the transverse cross-sectional area of the flow passage  236  to the check-valve  201  is about six times the size of the transverse cross-sectional area of the second flow line  223 ′. In other implementations, the transverse cross-sectional area of the flow passage  236  may be about ten times the transverse cross-sectional area of the second flow line  223 ′. 
     In accordance with some aspects, the port for the check valve subassembly  201  divides the pump body  215  into a first volume V 1  and a second volume V 2 . The first volume V 1  refers to the internal volume of the pump body  215  between the check valve port and a liquid interface surface of a piston  219  when the piston  219  is located at a lower-most point within the pump body  215 . The second volume V 2  refers to the internal volume of the pump body  215  between the check valve port and the liquid interface surface of the piston  219  when the piston  219  is located at an upper-most point within the pump body  215 . 
     When a piston  219  of the pump body  215  is located in the first volume V 1 , the piston  219  blocks the flow line  236  to the reservoir  235 . Accordingly, movement of a piston  219  within the first volume V 1  of the pump body  215  towards the second volume V 2  does not apply a suction pressure to the reservoir flow line  236 . Rather, such a movement of the piston  219  applies a suction pressure to the second flow line  223 ′, thereby causing a fluid sample to be withdrawn from the patient  217 . Continued movement of the piston  219  into the second volume V 2  of the pump body  215  unblocks the reservoir flow line  236 . As noted above, the difference in size between the check valve port and the second flow line  223 ′ causes the continued movement of the piston  219  to pull calibration fluid into the pump body  215  from the reservoir  235  instead of continuing to pull the fluid sample from the patient  217 . Moving the piston  219  back towards the first volume V 1  pushes the calibration fluid from the pump body  215  into the second flow line  223 ′ towards the sensor  214 ′. The calibration fluid pushes the fluid sample from the sensor  214 ′ back towards the patient  217 . 
     The calibration fluid mixes with the withdrawn fluid sample to a limited extent at a region where the two fluids meet. Fresh calibration fluid from the reservoir  4  mixes with spent calibration fluid to a limited extent at a region where the two fluids meet. As noted above, the dimensions of the flow lines  220 ′,  223 ′ inhibit mixing of fluids. Accordingly, any mixing occurs over a limited length of the flow line  220 ′,  223 ′ known as a diffusion barrier. The length over which such barriers extend will depend on the concentration of the fluids, the duty cycle of the pump module  216 , the size of the flow lines  220 ′,  223 ′, as well as other factors. A first diffusion barrier DB 1 ′ refers to a length beyond which the blood sample cannot diffuse into the calibration fluid. A second diffusion barrier refers to a length beyond which fresh calibration fluid cannot diffuse into the spent calibration fluid. Because of the position of the in vivo sensor  214 ′ and size of the first flow line  220 , the second diffusion barrier is extremely short and, consequently, is not shown. 
     In some implementations, the pump module  216  initiates a duty cycle of the sensor system  210 ′ by washing the sensor  214 ′ and flow lines  223 ′,  220 ′ in calibration fluid. In some implementations, the pump module  216  first moves in a “pull” direction through the second volume V 2  of the pump body  215  to draw fresh calibration fluid into the pump body  215 . In other implementations, the pump module  216  previously drew in fresh calibration fluid at the end of the previous duty cycle. The pump module  216  moves in a “push” direction to expel the calibration fluid. In some implementations, the pump module  216  expels sufficient calibration fluid to coat at least the first flow line  223 ′ and the test chamber  222  of the sensor  214 ′. In certain implementations, the pump module  216  expels sufficient calibration fluid to also coat at least part of the first flow line  220 ′. In one implementation, the pump module  216  expels sufficient calibration fluid to coat the entire first flow line  220 ′. After calibrating the sensor  214 ′, the pump module  216  moves in the “pull” direction draws a blood sample from the patient towards the sensor  214 ′ for analysis. 
     When the piston  219  of the pump module  216  moves in the “push” direction towards the lower-most point within the pump body  215 , the piston  219  pushes the fresh calibration fluid from the pump body  215  into the second flow line  223 ′. In some implementations, the second volume V 2  of the pump body  215  is at least as large as a total volume of the second flow line  223 ′ and the test chamber  222 . In one implementation, the second volume V 2  of the pump body  215  is as large as the total volume of the second flow line  223 ′, the test chamber  222 , and the first flow line  220 ′. In such an implementation, the pump module  216  expels sufficient fresh calibration fluid to purge all spent calibrant from the flow line and into the patient. 
     In certain implementations, the second volume V 2  of the pump body  215  is at least as large as the total volume of the second flow line  223 ′, the test chamber  222 , and the second diffusion barrier DB 2 ′. In such implementations, the pump  216  will expel sufficient fresh calibration fluid to wash these areas so that spent calibrant will not interfere with the sensor readings during calibration. As noted above, the first flow line  220 ′ and the second diffusion barrier are significantly shorter in sensor system  210 ′ than they were in sensor system  210 . Accordingly, the second volume V 2  of the pump body  215  in sensor system  210 ′ may be significantly smaller than the second volume V 2  of the pump body  215  in sensor system  210 . 
     When the piston  219  of the pump module  216  moves along the first volume V 1  of the pump body  215  in the “pull” direction, the piston  219  draws a blood sample from the patient  217  into the first flow line  220 ′. In some implementations, the first volume V 1  of the pump body  215  is at least as large as a total volume of the first flow line  220 ′ and the test chamber  222 . In certain implementations, the first volume V 1  of the pump body  215  is at least as large as a total volume of the first flow line  220 ′, the sensor test chamber  222 , and the first diffusion barrier DB 1 ′. In such implementations, the pump  216  will pull a sufficient volume of blood to flush the sensor test chamber  222  of calibrant before analyzing the blood sample, thereby enhancing the accuracy of the test analysis. As noted above, continued movement of the piston  219  through the second volume V 2  in the “pull” direction causes the second volume V 2  of the pump body  215  to fill with fresh calibration fluid. 
     To minimize patient discomfort, another aspect of the disclosure relates to using relatively low flow rates through the flow path. In certain implementations, the catheter  212  is capable of withdrawing blood or other fluid samples at a rate less than 100 microliters per minute. Indeed, in certain implementations, the catheter  212  is capable of withdrawing blood or other fluid samples at a rate less than 50 microliters per minute. Such low flow rates enable sample fluids to be drawn from low flow regions, such as capillary beds, thereby further reducing patient discomfort. Of course, conventional venous catheters and other types of catheters also can be utilized for withdrawing test fluids from a patient. In other implementations, other techniques for withdrawing fluid samples from a patient in medical applications (e.g., intracranial pressure (ICP), microdialysis and iontophoresis) also may be utilized. 
     The general system  210 ′ described above provides a simple and relatively inexpensive system for monitoring analyte levels, such as lactate levels, in a patient. Because the system  210 ′ has a minimal number of parts, the system is suited for disposability. The simplicity of the system  210 ′ also facilitates assembly and operation of the system. 
       FIGS. 2 and 3  illustrate one example implementation of a pump module  216  suitable for use with any sensor system described herein. The example pump module  216  includes a pumping mechanism  20 , a check valve  21  ( FIG. 6 ), and reservoir  4 . The reservoir  4  holds a calibration fluid including calibrant. For example, in some implementations, the calibration fluid may contain Ringers Lactate or other such infusion agents). In certain implementations, the calibration fluid includes an anticoagulant, such as sodium citrate. 
     In some implementations, the pump module  216  includes a sterilizable housing enclosing the pumping mechanism  20 , the check valve  21 , and the reservoir  4 . In certain implementations, the housing includes a first housing part  5  and a second housing part  15  that are secured together. In the example shown, the first housing part  5  is a lower housing that defines part of the pumping mechanism  20  (see  FIG. 4 ) and the second housing part  15  is an upper housing that defines the reservoir  4  and another part of the pumping mechanism  20  ( FIG. 2 ). In other implementations, an integral pumping mechanism  20  can be coupled to an integral reservoir  4 . In still other implementations, the reservoir  4  may be spaced from the pumping mechanism 20 as shown in U.S. Pat. No. 6,117,290, incorporated by reference above. Tubing  14  leads from the pumping mechanism  20  to a sensor (e.g., sensor  214  of  FIG. 1A  or sensor  214 ′ of  FIG. 1B ). 
     In some implementations, the pump module  216  is disposable. In certain implementations, the tubing  14  also is disposable. Indeed, in certain implementations, the pump module  216 , the tubing  14 , and an analyte sensor (e.g., the ex vivo sensor  214  of  FIG. 1A  or the in vivo sensor  214 ′ of  FIG. 1B ) form a disposable set assembly. A clinician connects the disposable assembly to a lactate monitoring system (e.g., see the controller  224  and other system components of  FIGS. 1A and 1B ) that, in turn, provides the data acquisition, storage, and display functions. 
     In certain implementations, the disposable set assembly is designed for low cost injection molding and low volume, partially automated assembly by means of ultrasonic or laser welding. Sub-assemblies of the set may be fabricated using transfer adhesive films or U.V. curable epoxies. In some implementations, the tubing  14  includes a 90/10 micro bore tubing. In other implementations, other types and sizes of tubing  14  may be utilized. 
     The pumping mechanism  20  includes a pump body defining an interior  11  in which fluid may be contained. In some implementations, the pump body interior  11  is divided into a first portion formed by the first housing part  5  ( FIG. 4 ) and a second portion formed by the second housing part  15 . In certain implementations, the first portion of the pump body interior  11  has substantially the same volume as the second portion of the pump body interior  11 . In other implementations, however, the first portion may have a greater or lesser volume than the second portion. A piston  12  is configured to move (e.g., reciprocate) through the passage  11  along a vertical axis A R  ( FIG. 4 ) to increase or decrease the volume of the pump body interior  11 . 
     In some implementations, a piston driver  13  is attached to one end of the piston  12 . In other implementations, the piston driver  13  is integral with the piston  12 . In certain implementations, the piston driver  13  is configured to slide along a track  16  provided at the upper housing part  15  (see  FIG. 3 ). In the example shown, the track  16  is external of the upper housing part  15 . The piston driver  13  is controlled by the control unit  224  ( FIGS. 1A and 1B ) to move the piston  12  axially within the pump body interior  11 . For example, the control unit  224  may move the piston driver  13  upwardly and downwardly along the track  16 . 
     The lower housing part  5  provides connector arrangement  10  by which the pump module  216  may connected to a lactate monitoring system (e.g., to a control unit  224  of  FIG. 1A ). In some implementations, the connector arrangement  10  defines one or more openings through which a fastener may pass to secure the pump module  216  to a surface. In other implementations, the connector arrangement  10  includes fingers, pegs, tabs, or other such members that are configured to interface with structure of the lactate monitoring system. The piston driver  13  also may include structure for interfacing with the lactate monitoring system. 
     The pump body has a first port  17  ( FIG. 3 ) coaxial with the piston  12  at which the outlet fluid line  14  is connected to the pump body to create the second flow path  223 ,  223 ′ of  FIGS. 1A and 1B , respectively. The pump body also has a second port  18  ( FIG. 6 ) defined at a circumferential wall of the pump body interior  11  at which the check valve  21  is connected to the pump body via a reservoir flow path  9 . As noted above, the reservoir flow path  9  to the check valve  21  divides the pump body interior into a first volume V 1  and a second volume V 2  (see  FIG. 5 ). In some implementations, the reservoir flow path  9  is located at an axial center of the pump body interior  11  (see  FIG. 3 ). In other implementations, the reservoir flow path  9  is located offset from an axial center of the pump body interior  11 . 
     Two components providing access to the reservoir  4  are located at the topmost portion of the second housing  15  on the pump module  216 . A first of the components includes a fill septum  1  and a second of the components includes an air vent  3 . The fill septum  1  provides a channel through which the reservoir  4  may be filled with the anticoagulant/calibrant fluid mixture during or subsequent to manufacture of the pump module  216 . In one example implementation, the fill septem  1  is a silicone-rubber fill septum  1 . 
     The air vent  3  provides a channel to allow air to be displaced from the reservoir  4  as the calibration fluid is either added (e.g., during manufacture) or depleted (e.g., during the normal operation of the pump module  216 ) without the need for complex valve mechanisms. In one example implementation, the air vent  3  is a non-woven Teflon® air vent  3 .  FIG. 7  illustrates one example implementation of an air vent  3  suitable for use with the pump module  216  of  FIGS. 2-5 . The air vent  3  includes a Gortex, non-woven, vent structure  41  and molded poly plug  42 . 
     As discussed above, the duty cycle of the pump module  216  includes a wash cycle, during which calibration fluid is provided to the sensor, and a test cycle, during which a blood sample is provided to the sensor. Accordingly, the piston driver  13  moves the piston  12  in a reciprocating pattern to create bidirectional flow of fluid through an outlet fluid line  14  during operation. In some implementations, the duty cycle is implemented over a time period of about 8 hours. In other implementations, the duty cycle is implemented over a longer or shorter period of time. The duty cycle may be repeated periodically to monitor trends in the analyte (e.g., glucose, lactate, etc.) levels of the patient. In some implementations, the duty cycle of the pump module  216  also includes a refill cycle during which the pump module  216  obtains fresh calibration fluid from the reservoir  4 . In other implementations, the pump module  216  obtains the calibration fluid during one of the wash cycle and the test cycle. 
     During the wash cycle, the piston  12  moves downwardly towards the first port  17 , thereby pushing a volume of calibration fluid towards the patient to provide a calibration and anticoagulant wash to the outlet fluid line  14  and to the downstream sensor (e.g., sensor  214 ,  214 ′ of  FIGS. 1A, 1B , respectively). In particular, the piston  12  pushes any calibration fluid contained in the pump body towards the first outlet  17  and into the outlet flow line  14 . The check valve  21  inhibits the calibration fluid from returning to the reservoir  4  through the reservoir flow path  9 . Pushing the calibration fluid from the pump body into the outlet line  14  causes the calibration fluid that was contained in the outlet line  14  to move towards the sensor. 
     During the test cycle, the piston  12  moves upwardly away from the first port  17  along the first volume V 1  of the pump body interior  11  to draw a patient blood sample and to “pull” the blood sample across the sensor where the blood analysis is taken. At the start of the second cycle, the piston  12  extends across the second port  18  and blocks access the reservoir flow line  9 . Accordingly, movement of the piston  12  through the first volume V 1  does not pull calibration fluid from the reservoir  4  into the pump body interior  11 . As noted above, the first volume V 1  of the pump body interior  11  is at least as large as a combined volume of the first flow line between the patient and the sensor, the test chamber within the sensor, and a diffusion barrier extending from the sensor along the outlet fluid line  14 . Accordingly, movement of the piston  12  through the volume V 1  is sufficient to pull a non-diffused blood sample through the first flow line and across the sensor. 
     During a refill cycle, the piston  12  passes the second port  18  as the piston  12  continues to move upwardly, thereby unblocking access to the reservoir flow line  9 . When the second port  18  is unblocked by the piston  12 , upward movement of the piston  12  through the second volume V 2  of the pump body interior  11  pulls calibration fluid from the reservoir  4  through the check valve  21  and into the pump body interior  11  (e.g., see  FIG. 5 ). As noted above, in some implementations, the diameter or transverse cross-sectional area of the reservoir flow path  9  is much larger than the diameter or transverse cross-sectional area of the outlet fluid line  14 . Accordingly, the differential pressure gradient between the two ports  17 ,  18  caused by continued upward movement of the piston  12  results in fluid flow through only the second port  18 . Therefore, upward movement of the piston  12  through the second volume V 2  fills the second volume V 2  with calibration fluid without further drawing blood from the patient. 
       FIG. 6  illustrates one example implementation of a check valve sub-assembly  21  suitable for use with the pump module  216 . The check valve  21  is located within the cylindrical passage  9  joining the pump cylinder  11  and the reservoir  4 . The check valve  21  includes a valve body  31 , a valve seat  32 , and a valve diaphragm  33 . A planar surface of the diaphragm  33  faces a wall or plate  36  defining one or more holes  35 . In the example shown in  FIG. 6 , the plate  36  defines one hole  35 . In other implementations, the plate  36  defines an array of holes  35 . In certain implementations, the holes  35  defined in the plate  36  are about 0.015 inches is diameter. In other implementations, the holes  35  may be larger or smaller. 
     Fluid flow is directed from the reservoir  4 , through the check valve  21 , and toward the pump cylinder  11  during the second cycle after the piston  12  has passed the second port  18 . In the example shown, fluid flow is directed toward the pump cylinder  11  when the piston  12  passes a chamfer  34  between the pump cylinder  11  and the reservoir flow path  9 . When the piston  12  reverses direction and begins to move towards the first port  17 , a diaphragm  33  is forced against a valve seat  32  covering the holes  35  in the plate  36 . Covering the holes  35  prevents flow into the reservoir chamber  4  during the “push” cycle of the piston motion. When the piston  12  clears the second port  18  during the downward movement cycle, the check valve  21  again allows flow to enter the cylinder  11  and fill the space behind the piston  12  as the piston moves towards the first port  17 . 
       FIG. 8-10  illustrates one example implementation of an ex-vivo sensor  214  suitable for use with the pump module  216  of  FIGS. 2-5  and with the sensor system  210  shown in  FIG. 1 . The sensor  214  includes a planar sensor  11  ( FIG. 9 ), an electrical connector skin mount  52  ( FIG. 10 ), and a fluid connector  51  ( FIG. 8 ). 
       FIG. 9  illustrates a detailed view of the fluid connector  51  of  FIG. 8 . The sensor  611  includes at least two conductive traces serving as an electrode array  613 . In some implementations, the sensor  611  is fabricated as a screen-printed array deposed on a polymer film. The electrode array is configured so as to be perpendicular to entry ports  612  that are configured to receive two tubular connectors of the fluid connector  51  of  FIG. 8  when the sensor  611  is mated to the fluid connector  51 . The printed electrode array  613  is patterned so as to provide two or more electrically isolated electrode pads on a facing plane common to the entry ports and aligned so that a fluid path channel  614  formed in the fluid connector portion of the sensor housing that links the two entry ports will completely traverse a portion of the electrode array in transit from one entry port to the other. The two entry port passages in turn provide connective means for two flexible tube components  66  of identical cross sectional dimensions. 
     A first of the flexible tube component  66  links the fluid connector portion of the sensor housing to a pump/reservoir assembly, such as reservoir  4  of  FIGS. 2-3 . A second of the flexible tube components  66  links the fluid connector portion of the sensor housing to a patient access port (e.g., of the catheter). In one implementation, the catheter is an I.V. Peripheral Infusion Catheter (PIC). The flexible tube component interface is provided at the anterior vertical face of the fluid connector in the form of two cavities that provide structure to receive the flexible tube components for bonding: to make the fluidics assembly, set the depth of insertion for the flexible tube components in relationship to the sensor interface, and provide positions for the entry port passages and the communicating channel between the two entry port passages  612 . Along the same axis of the entry port passages a mating feature  67  is provided for the guide rail boss feature of the electrical connector skin mount. 
       FIG. 10  illustrates a detailed view of the electrical connector skin mount  52  of  FIG. 8 . The electrical connector skin mount (ECSM)  52  is configured to provide electrical communication between the sensor  611  and the monitoring system. The ECSM  52  is affixed to the patient (e.g., by adhesive tape or by an integrated adhesive film patterned on the mounting surface  73 ). Distal to that mounting surface the ECSM  52  is configured with a guide rail boss feature  71  that carries two conductive spring pins  72  parallel to the mounting surface plane. The spring pins protrude beyond the posterior vertical surface of the ECSM sufficiently so as to pass through two guiding cylindrical passages so aligned as to provide access of the conductive spring pins to the output contacts of the sensor electrode array contained within the fluid connector. The guide rail  75  functions to support the fluid connector mounting process by the user by providing the initial alignment necessary to position the spring pins and direct them to the mating position with the sensor. A third feature of the ECSM  52  is a retention snap-latch  74  located at the posterior portion of the ECSM  52 . The retention snap-latch  74  mates to latch an opposing feature  67  provided on the fluid connector of the  FIG. 9 . 
     Additional details pertaining to example ex vivo sensors can be found in U.S. Pat. No. 6,117,290, the disclosure of which is incorporated by reference above. For example,  FIGS. 11-17  and the accompanying text disclose one example implementation of an ex vivo sensor  214  suitable for use with the sensor system  210  of  FIG. 1A . 
       FIGS. 11-13  illustrate one example implementation of an in-vivo sensor  214 ′ suitable for use with the pump module  216  of  FIGS. 2-5  and the sensor system  210 ′ of  FIG. 1B . As shown in  FIG. 11 , the example in vivo sensor  214 ′ includes a fluid connection  81  to a pump module  216 , a CCM fiber and connector harness  82  connected to the monitoring system (e.g., control unit  224 ), skin mount  83  with gel electrode pad on a proximal surface thereof for positioning of the in-vivo sensor  214 ′ at the patient&#39;s skin, a luer connection  84 , and a PIC catheter  85 . 
       FIG. 12  illustrates a longitudinal cross-section of the in-vivo sensor  214 ′ of  FIG. 11 . This view shows a CCM working electrode  90 , which resides within a catheter sheath  96 . The terminus of the sensor  214 ′ being sufficiently distal from the catheter sheath lumen  105  to limit the effects of diffusion between the blood sample and the calibration fluid. The fluid path through the indwelling catheter to the patient capillary access is routed through a molded component providing both an electrical connection and a fluid connection to the sensor system  210 ′. A fluid/electrical connector  93  resides at the distal port of the PIC Catheter  95  and is connected to the PIC Catheter by means of a standard Luer Lock component  97 . When connected and mounted to the approved patient access site (e.g., on the forearm, the back of the hand, or wrist) the CCM working electrode  90  is directly wired to the patient blood with a circuit made through a skin mounted gel electrode  98  and back to a lactate monitor through the conductor of  91 . 
     Additional details pertaining to example in vivo sensors can be found in U.S. Publication No. 2010/0252430, the disclosure of which is incorporated by reference above. For example,  FIGS. 6A-6C, 7, and 8  and the accompanying text disclose one example implementation of an in vivo sensor  214 ′ suitable for use with the sensor system  210 ′ of  FIG. 1B . 
     With regard to the foregoing description, it is to be understood that changes may be made in detail, especially in matters of construction materials employed and the shape, size and arrangement of the parts without departing from the scope of the present disclosure. It is intended that the specification and depicted aspects be considered exemplary only, with a true scope and spirit of the disclosure being indicated by the broad meaning of the following claims.