CA2630094A1 - Blood analyte determinations - Google Patents

Abstract

The present invention comprises methods and apparatuses that can provide measurement of giucose and other analytes with a variety of sensors without many of the performance-degrading pr.alpha.bfems of conventional approaches.
An apparatus according to the present invention comprises a biood access system, adapted to remove btood from a body and infuse at feast, a portion of the removed blood back Into the body. Such an apparatus also comprises an analyte sensor, mounted with the blood access system such that the analyte sensor measures the analyte in the blood that has been removed from the body fay the bfood access system. A method according to the present invention comprises removing blood from a body, using an analyte sensor to measure an analyte in the removed Wood, and infusing at ieast a portion of the removed blood back into the body. The use of a non-contact sensor with a closed system creates a system wSH minimal infection risk.

Description

8toort Analyta Determinations '#'echnical Field E00011 This invention relates to the field of the rTieasurement of lalood anaiytes, and more specifically to the measuren -ent of analytes such as glucose in blaod that has been temporarily removed from a botiy.
Sackground.Art [00021 More than 20 peer-revietived pubficatio-is have demonstrated that tight control of blood gÃricose significantly improves critical care patient outcomes. Tight glycemic control (TGC) has been shown to reduce surgical site infections by 60% in cardiothoraciesurgery patients and reduce overall ICU
rr3ortality by 40% with significarif redcc:tioi-ts in ICU morbidity and length of stay. 5ee~, e.g., i"timary Toriy, Oral pm- sentatiare at 2005 ADA anrtuaÃ, session titled dManageroeni of the Hospitalized Hyperglycemic Patier~t; " Vaii den Berghe et at., NEJM 20Ã31 ;346:1369. Historically, caregivers have treated hyperglyce.rrfia (high blood glucose) only when glttcose levels exceeded 220 --ngfdl. Based tiport recent clinical findings, however, extaerts now recommend IV insQlin admirtistratÃon to coiitrol blood g1iucose to within the norrrtoglycernic range {80-13 i3 mg/di}. Adherence to such strict glucose control regimens requires near cogtinuous monitoring of blood glucose and freqclent adjustment of insulin infclsiorF to achieve r}orrnoglycemia while avoiding risk of hypoglycemia (low blood glticose). En response to the demonstrated clinical benefit, approximately 50 fo of US hospitals have adopted some form of tight glycemic control with an additional 23% expected to adopt protocoÃs withifl the tlext 12 mNiths.
Furthermore, 36% of hospitals already using glycemic rrtartagement protocols in their ICUs plan to expand the practice to other units and 40% of hospitals that have riear-term plas3s to adopt TGC protrscol$
in the ICU also plan to do so in other areas of the hospital.
100031 Given the compelling evidence for improved clinica.l outcomes associated with tight giycemic control, hospitals are under pressure to implement TGC as the standard of' practice for crititat care and cardiac sorgeiy patieiits. Clinicians and caregivers have developed TGC
prat.ocols that use IV iiisutin administration to maintain normal patient gluaose levels. To be safe and effective, these protocols require frequent blood glucose monitoring. CurmntCy, these protocols iEivotve periodic removal of blood samples by nursing staff and testing on handhoÃd meters or blood gas analyzers.
Although hospitals are responding to the identified clinical neest, adoption has been. difticuÃt with current tectinoÃogy due to two principal reasons.
[0004] Fear of hvpQgtycemia. The target glucose range of 80-110 mg/dà brings the patient near clinical hypoglycemia (blood glucose less than 50 mg/do. Patients exposed to hypoglycemia for greater than 30 mintites have significant risk of neurological damage. IV instilirt administration with only intermittent glucose monitoring (typtcalÃy hoiarly by most TGC protocols) exposes patients to increased risk of hypoglycemia. In a recent letter to the editors of Intensive Care medicine, it was noted that 42% of patients treated with a TGC protocol in the UK experienced at least one episode of hypoglycemia. See, e.g.,1aiii Maolcenzie et af,, 'Tight glycaem#c controi;a survey of intensive care practice in iaiVe English Hospitals;" Intensive Care Med {2005} 31:'#136. In additÃnti; harsctheld meters require procedural steps that are often cited as a source of measurement error, further exacerbating the fear (and risk) of I

a.cciderttaliy taking the blood glucose levr:l too low. See, e_g., Bedside Glucose Tesfrng systerns, CAP
today, April 2006, page 44.
100061 l~urderrsarne rocQdure. 113iasf glycemic control protocols require frequerÃt glucose mtÃnttoring and insulin adjustment at 30 minute to 2 hour iritervals (iyplcatly houri,y) to achieve normoglycemia.
Caregtvers recagnlze that glur>crse: ctÃntml vaorÃlct be irnprcruedWit.b C011tirtrÃaus_ Or n~ a~ cc~nt.inucreÃs monitoring. Unfrzrturtateiy, existing glucose monitoring technology is incompatible with tbe need to obtain frei:{ueiit measurerrMentsr Using current technotogy, each measurement requires reÃnuvet of a blood sampie, performance of the blood gtÃ.icose test, evaluation of the resuit, determination of the correct therapeutic action, and fitially adjustment to the insulin infusion rate. High measurement frequency requirements coupled wi#h a labor-intensive and time-consuming test places 5ignÃficarrt strain on limited ICU nursing resoLrrces that alreacty struggle to meet patlerit care needs.
[00061 Deveic merit of Cozitirruous Glucosa Morritors. There has been significant effort devoted to ihe, development of in-vivo glucose sensors that ctarstirÃtacÃusty and autrrÃrraticaify monitor an indivfduahs glucose level. Such a deuice wotxld enable lnri'rviduals to more easily monitor their glucose iight. teve(s=
Most of the efFarts associated with continuous glucose morritaring have been focused on si:_Ãboutaneous glucose measurements. In these systems, the measurement dewice is implanted in the tissue crf the individual. The device then reads out agiucose concentration based upon the glucose concentration of the fltÃid in carttart with the measurement de.vice. Most of the systems implant the rieeWe in the subtutarreoas space anct the fluid measured under measurement is Irrterstitial fiuid, 100071 As used herein, a"crsnrtact glucose sensor' is any measurement :rievice that makes physical contact with the fluid containing the gtcrcose under measurement.
Standard glucnse meters are an example of a contact glucose sensor. in use a drop of blood is placed on a disposable strip fbr- the rieterrnirration of giucvse. An exai-nple of a glucose sensor is an etectrochamicat sensor, An electrochernicat seris+or is a device confrgused to detect the presence and/or measure the #eare# of anaiyte in a sample l4a electrachei-n'tcal oxidation and reduction reactions Rrsn, the .se#isor. These reactions are transduced to a electrical sig#1al that cari be correlated to an amount, concentration, or level of analyte in the sample. Another example of a glucose sensor is a microfluidtc chip or micro post technology_ These chips are a smati device with micro-sized posts arranged in varying numbers on a rectangle array cf specialized material which can, measure chemical canceniratiorrs. The tips of the micropcsks can be coated witl=i a biologioaliy active layer capable of i-neasustng concentrations of specl#ia lipids, proteins, antibodies, toxins and sugars. Micrapost:s have been made of Foturan, apf?oto defined glass. Another example of a glucose sensor Is a-fltÃora5cerrt measurement technology. The system for measurement is composed of a fluorescence sensing device consisting of a light source, a detector, a fluorophore (fir,forescence dye); a quencher aild an opiical poJymer matrix. VVheri excfted by light of appropriate wavelength, the fluorophore emits light (fiucresces). The intensity of the light or extent of quenching is dependent on the concentration of the cornpotands in the media. Another example of agtiÃcose sensor is an enzyme based monitaring system that irtciudes a sensor assembly, and an otiter membrane 5tÃrroiÃnding the sensor. Gerterally, enzyme based glucose monitoring systerrrs use glucose oxidase to aorrvert gitÃcose arÃd oxygen to a measurable end p.rociuct. The arnatrnt of end product produced is

2 proportional to the giucose concentration. Ion specific of electrodes are another example of aconiact giLrcose sensor.
E0008] As used herein, a"gtucose sensor" is a noncontact gtucvse sensor, a contact glucose sensor, or aiiy other instrument or technique that can determine the glucose presence or coricentration of a sarnpte. As used here:in, a"norrcontact glucose sensor is any measurement method that does r3ot.
require physical contact with the fluid containing the glucose under measurement. Example noncontact g1Lrc+ase sensors include sensors based upon spectroscopy. Spectroscopy is a study afthe compositicn or properties of matter by investigating light, sound, or particles that are ernitted; absorbed or scattered by the matter under investigation. Spectroscopy can also be defined as the study oÃt.he interaction between light and matter. There are three main types of spectroscopy: absorptiorr spectrosr,opy, emission spectrgscopy, and scattering spectroscopy. Absorbance spectroscopy uses the range of the electromagnetic spectrum i.n whÃctr a substance absorbs. After caiibra:tion, the amount of absorption can be relaie.d to the concentration of various corrrporir3rls through the Beer-Lambert law. Emission spectroscopy kases the range of the eÃectrorr#agrtet.ic spectrum in which a substance radiates, The substance first absorbs energy and then à radiates this energy as Ã#ght. This energy can be from a variety of sources including collision and chemical reaGtif3fls. Scattering spectroscopy measure certain physical characteristirs or properties by measuring the amount of light ttrat a substance scatters at cerEain wavelengths, inciderrce angles and polarization angles. One of the most useftià applications of light scattering spectras.copy is Rarrran spectroscopy bu# pctarÃzatiorl spectmscopy has also beer3 used for analyte measurements. There are many types of spectroscopy and the list below describes several types but should rtcrt be considered a definitive list. Atomic Absorption Spectroscopy i5 where energy absorbed by the sample is used to assess its characteristics. Sometimes absorbed energy causes tight to be released from the sample, which may be measured by a technique such as f(uorescer}ce spectmscofsy, Att.enuatetà Total F2efÃectarrce Spectroscopy is used to sample liquids where the sample is perietrated by an energy beam one or more times and the reflected energy is arlaSyzed.
Attenuated total reflectance spectroscopy and the related technÃque caÃterl frustrated multiple interna[
reflection spectrosoopy are used to analyze liquids. iWiect.rorr Paramagnetic Spectroscopy is a microwave technique based on splittiiig electronic energy fields in a niagnetic heid. It is used to determine structures of samples corrtainijig unpaÃred electrons. Electron Spectroscopy includes several types of electron spectroscopy, all associated with measr_rring changes in electronic errer-gy levels. Gamma-ray Spectrosccrpy uses Gamma radiation as the energy sotrrce in this type of spectroscopy, which includes activation analysis and Mossbauer spectroscopy. Ãnfrarer:i Spectroscopy uses the infrared absorption spectrusn of a substaiice, sometimes called its molecular fingerprint. Although frequerrtÃy ussd to iderstÃfy materials, infrared spectroscopy also is used to qcrantÃfy the number of absorbÃfig molecules. Types of spectrasoopy incÃude the use of mÃd-infrared Ãight, near-Ãnfrared light and uv/visibfe light. Fluorescerice spectroscopy uses photons to excite a sample which will then emit lower energy photons. This type of spectroscopy has become popular in biochemÃcal and medical applications.. !t can be Lased withr confocal microscopy, fluorescence resonance energy transfer, and fIuorescence lifetime imsgirrg. Laser 5pectrosccrpy can be used with many spectroscopic techniques to include absorption spectrtascopy, Ãirrcrescence spectrescofsy, Raman spectroscopy, and surface-enhanced Raman spectroscop}Ã, Laser spectroscopy provides inf'ormafion

3 about the interaction of coherent Ãight with matter. Laser spectroscopy generally has high resohtt"inn and se#7sitivity. Mass Spectrometry uses a mass spectrometer source to produce ions. Inforn-tation aboÃit a sample can be obtained by analyzing the dispersion of ions when they interact wtth the sample, generally usiiig the mass-to-charge ratio. 111iuitipiexor Frertueiisy-Moduiatert Spectroscopy is a type of spectroscopy where each optical wavciengih that is re:r>orcte:rt i.s encoded with a frequency containing the ariginai wavelength information. A waveler~gttt analyzer can then reconstruct the original spectrum.
Hadainard spectroscopy is another type of muitipiex.siaectroscopy. Ratnan spectroscopy uses Raman scattering of iÃght by molecules to provide informatiart on a sample's chemical compositiori atlcà molecular structure. X-ray Spectroscopy is a technique ii}votving excitation of inner electrons of atoms, which may be seen as x ray absorption. An x-ray fluorescence ernissiorz specfrum can be produced when an electron falls from a higher energy state into the vacancy created by the absorbed energy. Nticiear magnetic resonance spectroscopy analyzes certain atomic nucÃei to determine different local environments of hydrogen, carbon and other atoms in a rnotectaie of an organic compound. Grating or dispersive speo~trascopy typically records indiwÃduat groups of waveiertgths.
As can be seen by the number of methods, there are mtaitipie methods and means for rneastiring giticose in a non-contact mode.
to0#9] Note that the gitscose sensors are referred to via a variety of nomenclature and terms throughout the medical literature. As examples, giticose sensors are referred to in the literature as iSF
rnicrodiatysis sampling and online measurements, continuous alterr3ate site ineastrrernentsa tSiw fluid measurements, tisst#e glucose measurements, ÃSi" tissue glucose measurements, body fluid measuremerrts, skin measurement, sÃziii glucose measurements, subcutaneous gfucose measurements, extracorporeal glucose sensors, in-vivo glucose sensurs; and ex-vivo giticose sensors. Examples of such systerns include those described in US paterit 6990366 Analyte Monitoring Device a.iad Method of Use;
US patent 6,253,337 Ãrnplantabte Substrate 5ensor, US patent 6,201 ,98Ã3lrnpiantabie Medical Se-3sor 5ystem; US patent 6,477,395 irnpEantabÃe in Design Based Monitvriny System Having Improved Longevity Due to in Proved Exterior Surfaces; US patent 6,653,141 Polyhydroxyl-Substituted organic Molecule Sensing Method anci Device; US patent application 20050095602 Microfiuidic integrated Microarrays For Biological Detection; each ai=tt-e preceding incorporated by refere33ce herein.
[0010] In the typical use of the above glucose sensors require calibration before and during use.
The calibration process generally inuoives taking a eoriventivnai techrioiogy (e.g., fingersticÃc) measurement and correlating this measurement with the sensors current output or measurement. This type of cafibratioti procedure helps to remove biases and other artifacts associated with the itnpiantatitati of the sensor in the bod.y. The process is done upon initiaticsn of use and then again during the use of the device.
[i3047] Testing of CGMS systems in tbe iCU seitin . Since continuous glucose rrtonitoring systems (CGMS) provide a continuous glucose measurement, it: can be desirable to use these types of systems for implementation of tight glycemic control p.rotc+cols. The use of a continuous glucose monitoring systems has been investigated by several clinicians. These investigations have generally taken two different forms. The first has been to use the contÃntiotas glucose rnonitors in the standard manner of placing them in the tissue such that they measure interstitial gÃucQse. A
second avenue of investigation

4 has used the sensors in direct contact with blood via an extracorporeal blood toop. Summary inforrriatÃon from existiiig publications is presented below.
j0012] "Expertence with corftfnuous giucose rnonitoririg system amed'ÃcaI
Intensive care ur}it , by Goldberg at ai, Diabetes Technology and Therapeutics, Volume 6, Number 3, 2004, Figure 1 stÃcws the scatter plot of the 542 paired glucose rneasurernerit's. For the5e measurements the r vaiue was 0.88 overall with 63.4% of the measurement pairs feil within 20 mgldE af one anotherv,rbite 87.8% fell within 40 rng/dl. Additionally the authors state that severt of the 41 sensors ('Ã 70A) exhibited persistent malfunction priorto the study end point of 72 hrsurs.
[0013] "The use of two continuous glucose sensors during and after surgety" by Vr#esendsrp et at., Diabetes Techriotogy and Therapeutics, Volui-ne 7; Number2, 2005. I:n a summary conclusion the arfthcars' state that the technical performance and accuracy of continuocis gtcic:ose sensors need improvement before continuous glucose can sensors car# be used to impiernent strict gtycemic control protocols dtiriog and atter surgorys.
[0014] "Closer# loop glucose controt in criticaliy ilt patients using coMÃnuous glucose monitoring system in real-time", by Chee et a3, IEEE transactions on Ãnfomiation technology in biomass and, votume 7, Number one, March 2003. The authors prQVide a surnmary rammenttbat improvement of reai-t'-.me sensor accuracy is neected. In fact the actual accuracy' of the resuEts ger#erated: showed that 64.6% of the sensor readings wouid be clinically accurate (zone b) while 28.8 lo would [ead to in no treatment (zone as illustrated Ãn Figure 2. The aothors state that the accuraoy of subGutaneflusty measured glucose is (lependent "on equilibration of glucose concentration to be reached before 1SF, plasma and whole blood, takiEig irtio account a possible time delay. Skin perfusion on the site of the $ensor, iinsertion differs from patient to patient. Most patients admitted to the ICU have a degree of perÃpheral edema and rilucase tnG11itaring based cn !SF readings under such coilditions would be subjected to variation in tSF -p#asrna - whole blood equilibratiors. The proiaterrt is likely exacerbated by non-arnbuiatory patients with little dynamic circulation of fSi" in the subcutaneous spa<,e..
j0015] Probierns with Existing Ga9111S. The present invention can address variotas problems recognized in the use of OGMS. The pei-Forrnance of existisyg OGNÃS: when placed in.tbe tissue or ali extracorporeal blood clrcuit Is timfÃ:eÃI. The source of the performance iimitation can be segmented int:o several discrete error sources. The first is associated with the actual performance of tlie sensor overtirne<
while the secor7ei error grouping is ass-ociated wfth the physiology assumptions t3eeded for accurate measurements.
.[00161 Genera# performance (irniiations; in a sii-nplistic sense electrochemical or enzyme based sensors use glucose ox#da.se to convert gkacose and oxygen to gtuconic acid and hydrogen peroxide. An electrochernicai oxygen detector is then employed to meastire the conceiitration of remaining oxygen after reaction of the glucose; thereby providing an inverse measure aftbe glucose concentration. A
second enzyme, or catalyst, is optimally included with the glucose oxidase to catalyze the decomposition of the hydrogen peroxide to water, in ocxierto prevent interference in measurements from the hydrogen peroxide. In operation the system of measuring glucose requires that glucose be the rate timiting reagent of the enzymatic reactiort, When the glucose rneasurement, system is used in conditions where the concentration of oxygen can be limited a condition of "oxygen deficiency" r-an occur in the area of the enzymatic portion of the system -and resril#s in an inaccurate determination of giticose conce:ntration.
i"crther, such an oxygen deficit contributed other performarrce related problems for the serisor assembly, including diminishsd sensor responsiveness and undesirable electrode serrsitivity.. Intermittent inaccuracies can occur when the amount of oxygen present at the enzymatic serisor varies and creates conditioris where the arnount of oxygen cait be; rate lirnit.irÃg. This is parficularly problematic when seeking the use the sensor technology on patients with cardiopulmonary ccrnprornise.
These patients are poorly perf.,sed and f-nay not have adequate oxygenation.
[04171 Performance over tirra.e: in many conditions an electrochemical sensor shows drift and reduced sensitivity over time. This aÃteration i'n perforrr#a:nce is due to a multitude of issues which cati include: coating of the sensor membrane by albamin and fibrin, reduction in enzyme efficiency, oxidation of the sensor and a variety of other issues that are not completely understood. As a result oithese alterations in sensor perPcrrna.nce the sensors must he recalibrated on: a frequent basis. The calibration procedure typically reqraires the proGurernent of a bisxrscl measurement and a correlation of this measurement with the sensor performance. If a bias or diftereiice is present the implanted sensar's output is modified so that there is agreement between the value reported by the sensor and the blood reference. This process requires a separate, extemai measurement technique and is quite cuÃrrbersome to implement, [0018] Physiological assumptions: for the sensor to effectively represent blood gliicose vali$Ees a strong correlation between the glucose leveis in blood ar7d subcutaneous interstitial fluid must exÃst. If this relationship does not exist, a systematic error will be inherent in th:e sensor signal with potentially serious consequences. A rz.omber of publications have shown a close correfation behyeerr glucose levels in blood and siibcutarreous interstitial fluid. However, most of these investigations were performed under steady-state conditions only, meaning s1ow changes in blood glucose (<1 rr#gldVmin). This restricticn on the rate of change is very retevarit due to the compartmerrtal#zatior3 that exis.ts betweer3 the blood and iliterstitial fluid. Although there is free exchange of glucose between plasma and interstitial fluid, a change in blood glucose will not be irnmediately acocrm panÃed by an immediate change of the interstitial fluid glucose under dynamic conditions. There is a so-called physiological lag time. The physiological lag t.irrre is influenced by many parameters, includir~g the overall perfusion atttre tissrae, l.n coriditians where tissue pertusier is poor and the rate of glucose change is signfficant the physÃologicaf lag can become very significant. In these condltioiis the resulting differerrce between interstitial glucose and blood giLrcose can become quite large. As noted above the overall cardiovascular or perfusion status of the patient can have significant influence on the relationship between iSF glucose and whole blood glucose. Since patients in the interfsive care unit or operating room typically have some type of cardiovascular compromise the needed agreement between iSF gtttcose ar~d whole blood is not present.
.(0019'] Additional understanding with respect to the calibration of continuous glucose monitors can be obtained from the following references. US patent 7,029,444, Real-Time SelfAdjLrsting CalibratiQn Algorithm. The patent defines a method of calibrating glucose monitor data that utilizes to reference glucose values from a reference source that has a temporal relationship with the glucose rnonitardat,a.
The method enables calibrating the calibration characteristics using the reference glucose valties and th-e corresponding glucose monitor data. US patent application 2005/0143635 System and Method for Sensor Recalibration. "t"he patent application described a methodology for sensor recaÃÃt3raticsn utilizing an array of data which includes historicat as weii as recent data, such as, blood glmose readings asid sensor electrode readings. The state itz the appÃicatiorz, the accuracy of the sensing system Is generally limited by the drift characteristics of the sensing eiemeftt over time and the amount of envircnmeiital noise iotrodticed into, the output of the sensing element.. 'f'o accommoctate the inherent drift in the sensing element in the noise inherent in the system environment the sensing system is periodica.iÃy calibrated or recalibrated, j0E1201 Additional understanding with respect to sensor drift can be obtained frorn the following refereRices. ArÃieÃe by Gough et al. in Two-C3Ãmensiraiiaà Enzyme Electrode Sensor for Glucose, VOl. 57, Analytical Chemristry pp 2351 et seq (1985). US paferit 6: 477, 395 tmplas7tabÃe Enzyme-based Monitoring System Havirxg Improved Longevity Due to Improved Exterior Suffaces. The patent describes an implantable enzyme based rnonitoring system having an outer membrane that resists blood coagulation and protein bindÃrtg.. In ttte, bac[cgrottnd of the invention, coÃt#mtis I and 2 the aut.t7ars describe in detail the limitations and problems associated with enzyme-based gtucose monitoring systems.
[0021] The operation of many of the embadiments disclosed herein involves the use of a maintenance #iuic#. A maintenance fluid is a fluid used in the system for any purpose. Fluids can include saline, lactated ringers, mannitol, amicar, isolyte, heta starch, blood, plasma, serum, platelets, or any other fluid that is infused into the patient. In addition to fluids that are infused into the patient, mainten.arECe fluids can include fluids speci#icatÃy used for caEibratitig the device or for cleaning the system, for other diagnostic purposes, and/or can incÃtsde fluids that perform a combination of such fundicsns.
[0022] Glucose sensors, both contact and noncontact, have different capabilities avitts respect to making acctirate measurements in moving blood. For example, most strip based rneasÃ.tremet7t technologies require an enzymatic reactioti with blood and therefore have an operation ir3compatible with flowing blood. Other sensors can operate in a mode of estabiishling a constant output in the presence of flowing btoor#. Noncontact optical or spectrascopic sensors are espec"ia[Ãy applicable to coriditi?ons where the blood is flowing by the fact that they do not require an enzymatic reactiosi. For the blood access system describert herein, one objective is to develop a system that does not result in blood cÃotting.
Generally speaking blood that is stagnant is more prone to clotting than blood that is moving. Therefore the use of rneasurernent systems that do not require stationery blood is beiie#'fciai. This benefit is especiaEÃy relevant if the blood is to be re-infused into the patient, C00231 In an instrurne3it that operates In the i-ifensÃve care unit oii crEtica#Ãy ill patients, infection risk is an important consideration. A closed system is typically desired as the system has no mechanism for external entry into the flow path atter initial set-up and during operation.
The syste,'n can fuiictÃon withotit any opening or closing orthe system. Any operation that "opens"the system is a potential site of irliection. Closed system transfer is defined as the movement of sterile prodzicts from one container to another in which the containers olosure system and transfer devices remain intact throt,*ghout the entire transfer process, compromised only by the penetration of a sterile, pyrngers-free needle or cannala through a designated closure or port to effect transfer, withdrawal, or delivery. A closed system transfer device can be effective but risk of infection is generally higher riaae to the mechanical clos{ ires typically t.ised.
[00241 In the development of a glucose roeasureinent system for frequent ineascrerr#ertfs Ãi3 the intensive care ciiiit, the ability to operate in a sterile or closed manner is extremely important. In the care of critically iÃ1 patients tht; ctcsire to auoict the cl.eveloprnent of systemic or locaiized infections is considered exlremely important. Therefore, any system that can operate in a completely closed manner without access to the peripheral erivirorimerrt is desired. For example, blood glucose measurement systems that require the removal of blood from the patient fbr glucose determination result in greater infection risk due to the fact that the system is exposed to apotectiaily non-sterile environrnertt lbr each measurement. There are many techniques to minimize this risk of infection but the ideal approach is simply a system that is completely closed and sterilized. With respect to infection r#sic, a noricontact speciroscopic glucose measurement is almost irl.eal as the rrteasuremeot is made with light which is able to evaitaate the sample without any increase in infection risk.
Disclosure of Invention [0025] The present invention is related to US patent applications 601791,719 and 601737,254, each of which is incorporated herein by reference. The present invention comprises methods and apparatuses that can provide rneastirerneat of glucose and other analytes with a variety nfseosors without many of the performance-degrading problems of canventionai approaches. An apparattis according to the present invention camprises a blood access system, adapted to remove blood troErr a body and ir7tuse at least a portion oftkte removed blood back into the body. Stich an apparatus also comprises an analyte sensor, mourited with the blood access sys.tem such that the analyte sensor measures the analyte in the blood that has been removed from the body by the blood access system. A method according to the present invention comprises removing blood from a body, using an analyte sensor'to measure an analyte in the removed blood, and infusing at least a portion of the i'emoti+es1 blood back into the body. The use of a non-contact sensar with a closed systern creates a system wili minimal infection risk. Advantages and novel features will become apparent to those skilled in the art upon examination of the follotnrÃng ttescrÃption or can be learned by practice of the invention. The advantages of the invention can be realized and altained by mearzs of the methods, instrumentation architectures, and combinations specifically described in the disclosure and in the appended claims.
Brief Description of Drawings (0026] Figure I is a scatter plot of 542 paired glucose measurements from Experience with continuous glucose rnctnitoring system a tneciical intensive care oeft", by Goldberg at a(, i:7i-abetes Technology and Therapeuties,Volume 6, Number 3, 2004.
Figure 2 is an ilitrstration of error grid analysis of glucose readings_ Figure 3 is a scllematic illustration of an example embodiment of the present invention compri5ing a blood access system tisirrg a blood tlow loop.
Figure 4 is a schernatie illostratiore of a blood loop system with a peristaitic pump.
Figure 5 is a schematic illustration of a blood access system implemented based upon a pt3ll-pt#sh mechanism with a second circtilt provided to prevent fluid overlaac#.
Figure 6 is a schematic illustration of a blood access system based upon a pulÃ-push mechanism with a a second circuit provided to prever<t fitsicl overload.
i"igure 7 is a schematic iÃlusiratioii of a blood access system based upon a pulÃ-push mechanism.
Figure 8 is a schematic iÃir.rstratiort of a blood access system implemented based upon apull-push mechan#sm witil a second circuit proviÃted to prevent fluid overioad.
Figrare: 9 is a schematÃc illustratiorz of an example errtboctirrient that.
ailakvs abloocà sample for measurement to be isolated at a point near the patient and then transported to the instrument for measurement.
Figure 10 is an illustration of the control of the blood volume and the integration of the total amount of giLicose measured.
Figure t 1 is a schematic illustration of an example embodirnent that allows a blood sample for measurement to be isolated at a point nearihe patierat and then transported to the Ãnstrerrkent for measurement through the use of leaciing aiitt the following air gaps.
Figure 12 is a schematic illustration of an exam-pte embodiment of the present invention.
Figure 'Ã 3Ãs a schematic illustration of an example embodiment of the present invention.
Figure 14 is a schesrtatir, liltistratÃar# of an example embodimer*t of the presetlt inventican.
Figrire 15 is a schematic illustration of an example embodiment of the present invention, Figure 16 is a plot showing the relationship between pressure, tubing diameter and blood fraction.
Figtare 17 is a plot showing the relationship between pres5ure, tubing diameter and blood fraction.
Figure 18 is a schematic illustration of an example embodiment of the present inverition.
Figure 19 is a schematio iliiistration of an example embodiment of the present inverttion.
Figure 20 is a schematic illustration of an example embodiment of the present inventior}.
Figure C'Ã is a schematic illtistration of the operation of an example embodiment ofthe present invention.
Figure 22 is a schesrtatta ÃIlustr-ation of the operatiori of an example emt*dirr3ent of the preserit irivention.
Figure 23 is a schernatic Ãilustration of an example embodirrrer#t of the present inveritiflr}.
Figure 24 is a schematic illustration of an exar-nple embodiment of the present inventÃoil.
iwllades forCa3rryi;ng Out the tnverttion and Industrial Appticakritity L00271 The present inventiori comprises methods aiid apparatuses that can provide measurerneiit ofglocose arid other analytes with a varte#y ai'sensors without many ofthe pe.rt"armance-ciograding problems of conventional approaches. An apparatus according to the present invention comprises a blood access systern> adapted to remove blood from a body aiid infuse at least a portiori of the removed blood back into the body. Such an apparatus also comprises an. analyte sensor, mounted with the blood access system such that the analyte sensor measures the aiiaÃyte in the blood that has beeii removed from the body by the blood access system. A method according to the present invention comprises removing blood from a hody, r.#sing an analyte sensor to measr,#re an analyte ir3 the removed blood, aryd inftising at least a portion of the rernoverl blood back into the body..
E00281 The performance of the analyte sensor in the present invention can be dramatically improved compared with conventional applications by minimizing var+ous issues that contribute to degraded sensor performance over tirrre and by providing for cleaning and cal:ibratifig the rneas rement sensor overtime. The physiological tag problems associated with canventiarlal #isstie rneasrFrements can also br; reduced with the present invention by making a direct measurement in blood or by ensiiring that there is appt-npriate agreetne4it between the tSF git-RCose level and tttat in -wt=tofe btood.
E00231 Sorne embodiments of the present imtetztiot; provide for ef9'ective cleaning of the sensor. if effeotively cleaned at the end of each measureE'nent, the amou-it of sensor fouling and/or drift can be mir<iFnizr-.ct. Saline or aricather physÃologic..aily compatibte solution can be used to cioan Me sensing element.
E00301 A typicai glucose sensor used relies on ag[ucase-d:ependent reaction to meastsre the arnour-# of glucose present_ The reaction typically uses both oxygen and gIt3cose as reactants. If either oxygen or g#ucctse is not present, the reaction can not proceed; some embodiments of the present invaritiort provide fortotal removal of one orthe atherto allow a zero poirit calibration conctition. Saline or another physlologicai compatible solution that does not contain gicicrsse could be used to eÃfec#ivety create a zero point calibration cortdition.
[00311 There can be Ãimitation5 associated with a x.e-m point calibration so that ot~e crtay t3e.sire to tise a calii;irati4r- point witti a gicimse vaitte above zero and preferably mvitttin the physiological range, Some embodiments of the present invention provide for such a calibration by exposing the sensor to a glucose contairting solution with a known glucose cortcentratior#. This can effectrveiy recalibrate the sensor and improve its accuracy. The ability to make frequent recaiiioratÃons enables a simplistic approach to maintaining orrerall sensor accuracy.
[00$21 In many medical laboratory measurement products a'tvwo point calibration is used. Some embodiments of the present invention provide two types of calibrations to pro'Ode aWvo point calibration capabiiity. A two point caf#bratioEt can allow both Was arid slope to be effectively determined and rnitigated.
100331 In practice the degree or amount of physiological lag observed between 15Fgltarose levels in whole blood glucose levels creates a signiÃicant errorsotsrce. Some emboctirrterits of the present inverttiofi reduce this source of error by placing the sensor in direct contact wfth blood.
[0034] Recognizing the several error sources, the present invention provides an accurate continuous or set-nicaaitinuous blood glucose measurement system for use in applications such as the intensive care unit. Some embodiriterits of the presesit iriverfÃiort place blood in contact with a sortsit7g mechanism for a det'ined measurement period arid then clean the sensor.
Following cieaniÃtg of the ser-sor. a calibration poirit or points can be established. The present invention wntemptates a variety of blood access circuits that can enable the sensor to be cleaned on a periodic besis and can allow for recalibration; illustrative examples are described below. In addition to providing amer#3anism for improved sensor performance, the disclosed blood access systems can also provide methods for occiusiort management, minimization of biood loss and m#riirnization of saline used for circuit cleaning.
.Et30351 The example embodiments generally show a blood access system with the ability to control fttÃid flows at a location removed from the blood access console and near the patient The ability to control fiLtid flows at this remote lstcatiort does not necessitate the use of a mechanicat valve or other similar apparaitÃs that similarly directs or control flow at a point near the patient.
Additionally it does ntit require ntirse or other htarrtan intervention. For rrtultiple reasons, incltjding safety and reiiabiiity, it is desirable not to have a mechanical device, wires, or electrical pokqer near the patient. As shown in many example ~~

embodiments, this capacity is enabled through the use of a prjmping mechanism that provides for both fluid stoppage aaid rnovemerrt. Additional capabilities are provided by biriirectional operation of the purnps, and by eperatiost at variable speeds including complete stoppage of f'iuirt itow fluid flow. As used in the disclosure, operation may be the use of the pump as a ftaw control rtevÃce to prevent flow. As si3owm in the example embodiments these capabilities can tio providect through peristattic pUrtrp-, and syringe pumps. It is recognized by one of ordinary skill in the art that these capabliÃties can also be provided by other ff cid handling devices, ificlcrding as examples linear ff{7ger" pumps, vatveless rotating and reciprocating piston metering pumps, piston pumps, lifting pumps, diaphragm pumps, and centrifugal p.umps. "Plunger" purrrps to include syringe pumps as well as those that can clean a long thin flexible piece of tubing are considered. These types of pluriger pumps have the advantage of remo'Virlg or transporting the fiuid without the need for a following fluid volume. For example, no f4llawr volume is required when using a syringe pump.
[00361 The example embodiments generally show a sensor in contact with a bioort access system.
The sensor can be immersed or otherwise continuously exposed to fluid in the systcm. It can also comprise a noncontact sensor that interacts with fitÃict in the system. It can also comprise a sensor remote from the blood access system, where the sertsor element in the example comprises a port or other sampling mechanism that allows a sriltat?ls sample of fluid from the system to be e.xtracted and presented to the remote sensor. This type of sampling can be trsert with existing technology gltjcose meters and reagent strips.
[00371 Exannple Embodiment comprising a sensor and a fluid management system.
Figure 12 is a schematic illustration of an exarnple embodirnent of the present invention corrrprisinga sensor and a flcaid management system. The system ccsrrrpÃises a catheter (cr similar blood access detrÃce) (12) in fluid cominuni:cation with the vascular system of a patient.
A t,ubi#ig extension (if required) extends from the catheter= (12) to a junction (10). A firs.t side of the junction (10) connecfs ~fith fluid transpor-t apparatus (2) such as tubing (for referei-rce purposes called the "leÃt side" of the blood system);
a second side of the;unetion (10) connects with fluid transport apparatus (9) such as tubing (W reference purposes called the "right side" af the blood system). A sensor (1) mounts with the left side {2} of the blood loop, A fluid management system (21) is in fluid communication with the left side (2) and right side (9) of the blood system. In operation, the fluid management system (21) aets to draw blood from the patient through the catheter 12 and into the left side (2) afthe blood system to the sensor 1. The sensor 9 determines a blood property of interest, for example the concentration ot'glucose in the hlaod. The fluid management systern (21) caii push the blood back to the patieriY#hrough the left side (2) ot=the blood system, or can further draw the measured blood into the right side (9) of the blood system, and through jr.rncticrl (10) to catheter (12) and back into the patient.
[00381 The fluid management system (21) can control the fluid volume flow and fluid pressure in the left (2) and right (9) sides of the blood system to control whether fluid is being withdrawn from the patient, infirsed into the patient, or neither. The fluid management system (21) can also comprise a source of a stritable fluid such as saline, and manage fluid flow in the system such: that saline is circulated thror3gh the left (2) and right (9) sides to fitish or clean the systerrr. The fluid management system can further comprise an outlet to a waste container or channel, and manage fluid flow such that used saline, blaor3/salirre mix, or blood that is not desired to be returned to the patient (depr;nding on the requirements of the appiicatioti) is delivered to the waste contaiiier or channel.
[00391 Example Embodiment camprÃsing a blood loop system with a syringe gump.
Figure 3 is a schematic illustration of ari example embodiment of the present iriuentian comprising a blood sccess system using a blood flow loop. The systerirr rornprises a catheter(or similar blood access device) (12) in flilid communication with the vascular system of a patient. A
tubing extension (11) (if required) extends frvm the catheter (12) to a junctiori {10}.A first side of the junction (10) connects with fluid transport apparatus (2) such as tubing (for reference ptsrposes cailed the "left sicÃe" of the blood loop); a second side of the junction (10) connec#s with ituicà transport apparatus (9~) such as tubing (for reference purposes called the "riglY# side" of the blood loop). A sensor measurement ce#t (1) and a pressure measurenient clevice (3) mount with the left side (2) of the blood lvop. A peristaitic pump (8) mounts between the left side (2) and the right side (9) of the biocd Ioap. A.
pinch valve (42) ("pir7ch valve"
is used for convenience throughout the description to refer to a pinch valve or any suitable flow control mechanism) mounts between the left side (2) of the blood loop and a jtinctivn (13): controlling fluid communication therebetvdeen. A pinch vaive (43) mounts between the junction (13) and a waste channel (7) (such as a bag), controlling Mrid communication therebetween. A
pinch valve 41 mounts between the jÃtnctian(I 3) aiici; a srurce af wa5h t(t-ict (0) (such as a bag of saline), cor#troliÃr~g fluid flow therebet reen. A syr'trrge pump (5) mounts in tiuici communication with the junction (13), The system can be operated as described belavr. The descrlption assumes a primed state of the systern whereirl saline or another appropriate fluid is used to initially fill sorne or all channels of fluid communication. Those skilled in the art will appreciate that other start conrlÃtioris are possible. Note that ' lett side~ and 'right sÃde" are for convenience of reference only, and are not intended to limit the placement or disposition of the blood loops to specific Ãeft-right relationship.
[0EÃ40] Blood sam te and E-neasurernent process. A#Ãrst sample draw with the example embodiment of Figure 3 can be accomplished with the following steps:
à . Syringe purnp (5) initiates a draw along the left side (2) of the blood loop.
2. The blood interacts with the sensor measurement r-ell (1). The volume of the catheter (12) and extension tubing (11) can be determined from the syringe pump (5) operating parameters and the time until blood is detected by the sensor measurement cell (1) and used for future reference.
3. Sensar measurei-nent.s can be made as the blood moves through the measurement cell (1).
4. As blood nears junction (13) the system can be stopped artcà the saline thatvs+as drawn into the syringe pump (5) placed in waste bag (7) by the appropriate use of pinch valves (43, 42,41).

5. Blood drawn via the left side can continue vi.a the withdrawal of syringe (5).

6. Withdrawal of blood by the syringe, either fL#Ily or partially, is stopped.
Sensor sampltsig of the meastrrement cell can be continued or stopped.

7. Initially saline and then blood is re-irrfusec3 into the subject via combination of peristaltic pump (8) and syrinqe (5). The tvro pump mechanisms operate at the same rate such that blood is moved along the right side (3) of the circuif only. Note, blood does not substatitÃalty pngress up the left side (2) of the eircuit btit is re-infused past junction (10) and into the patienf.
One or more weight scales (not shown) can be used to measure the waste and saline solution together or irlrtependently. Stich weight scales can allow rest time compensation between the pumps, e.g., to ensure that the rates rnatch, or to ensure that a desired rate difference or bias is maintained. For insfatzoe it can be desirable that a certain volume of satiiie be infused into the patient durityg a recircuiation cycle. In such an application, the combined weight of the waste and satine bag shoa(ct decrease by the weigb.t of tttc desired votume of saiine. If the weight or wc;ight~.s do not correspond to the expected weight or weights, then one or both pumps car- be actjusted.
If a net zero balance is required the,i the combined weight at the stail of recircuiatfon mode and at the eiid of recircoiation mode should be the same; again, one or both pumps can be adjusted to reach the desired weight or weights.
[0047) Sobsa uent BIood Sam ". For subsequent samples, the blood residing in the catheter (12) and e>dension tLibirEg (11) has already been tested atid cati be cosisidered a 'tusecir sample. The example embodiment of Figure 3 can prevent this sample from contamirxating the next meascrement, by operation as foitows.
1, Syringe pump (5) and tserist.ettic pump (8) initiate the blood draw by rtrawi;7g blood tsp throtigh the right side of the blood loop, 2. The withdrawal continues until all of the sed blood has passed junction (1{3). The volume determination made during the initial draw can enable the ac-curate determination of the location oÃ'ihe used blood sat-npte.
3. Once the used sample has passed the jtsr*otion (10), the peristattic pump

(8) can be turned off aE3ct blood vsriihdrawEZ via tkie left side (2) of the circuit. Sensor measurement of the blood can be made during this withdrawal.
4, The withdrawal prooess can continue for a predetermined amoont of time.
Following completion of the sensor sampling (or overlapped in time), the blood can be re4nfused into the patient.
The blood is re-infused into subject via cornkr# atiorr of peristaltic pump (a) and syringe pump (6). The two, pumps operate at the same rate such that blood is moved along the right side

(9) of the circuit oni,y. Note, blood does not progress up the left side (2) of the circuit but is re-inÃosed past,{uaction (10) and into the patierit, There is no requirement that the withrÃiawat arzd infusion rates be the sarne for this blood loop systeFn.
[0042] Cieanin of sstem and saline catibration rocurement. A cleaning and caÃibration step cari clean the system of any residual protein or blood buifÃ#-up, and cen charactertze the system; e.g., the performance of a meast-reme;it system can be characterized by making a saiirie calibration reference measurement, and that characterization used in error reporting, instrument self tests, and to enhance the accuracy of blood ineasurerrtents. The cleaning process casi be in##iated at the end of a standard blood sampling cycle, at the end of each cycle, or at the end of each set of a predetermined number of cycles, at the end of a predetermined time, when some peÃfiormenee characterization indicates that c#eaning is rectciired, or some combination thereof. A cleaning cycle can be provideci with the example embodiment of Figure 3 with a method such as the following.
I . The start condition for initiation of the cleaning cycie has the syringe substantially depressed following infusion of blood into the patient.
2. Pinch valve (42) closed: and pinch valve (41) opened and syringe (5) withdraws saline from the wash bag (6).

3, Following the withdrawal, pinch valve (42) is opened and (41) and (43) are ctosed.
4. Syringe pump (5) pushes saÃine towatrà patient at first rate while peristaltic pump (8) operates at a second rate equal to one half of'the first rate. This rate relationship means that saline is infused into the two arrrrs for the loop at equal rates and the blood present in the system is re-infused iz7to the patient.
5. Following completion of the saline infusion, both ar.rns of the loop system (2, 9) as weÃ1 as the tcii3iny (11) and catheter (12) are filled with satiiie.
6. Pinch valve (42) is closed and peristaitic pump (8) is turned on in a vibrate mode or pulsatile fiaw mode to compÃeteÃy clean the loop.
7. Pinch value (42) is opened. Syringe begins pull at a third rate and peristaltic pump pulls satirÃe at fourth rate equal to one half of the third rate. This process effectively t#3#s the entir=e toop with blood while concurreEitÃy placing the sati.ne used for cieataing into the syringe (5). Sensor measurements cAc occur after the bÃorsdJsaÃine junction has passed the rrteasurement reiÃ.
8. Pinch valve (43) opened and pinch valve (42) closed and saline is infused into waste bag (7).
9. Pinch valve (43) closed, (42) opened and blood pulled from patient ar~d back to measurement mnd'e..
[0043] Charact.eristics ef the exafflpt_e_ embodlment. The example embodiment of Figure 3 allows sensor EneaSurernertts of blood to be made on a very frequent basis in- a s.emi-continuous fashion. There is little or no blood loss except during the cleaning cycle. Saline is infused into the patient only during cleaning, enti very Ãittle setine is infused irtta the patient. The gas dynamics of the system can be fully equilibrated, allowing the example embodiment to be used with arterial blood.
There are no blood/saline junation complications except during oÃeaning. The system cantains a pressure monitorthat can provide arterÃaf< central venous, or pulmonary aEtery catheter pressure measurements a:#ter compensation for the pull and push of the blood access system. The system can compensate for differer3t size catheters through the volume pulled via the syringe purnp. The system can determine occlusions or partiai occlusions with the blood sensor ar the pressure sensor. i:3ue to the flexibility in operaticn and the direction of flawt the system can determine if the occlusion or partial occlusion is in the Ãeft. side of the circuit< the right side of the oircuit or in the tubing between the patient and the T-junction. If the ocoÃusÃen is in the right or left sides, the systein mn enter a cleaning cycle with agitation and remove the clot iauitd-up. If a microembolus is detected the system can initiate a mode of operation such that the problematic blood is tatceti directly to waste. The system can theii enter ijito amcde such that it becomes saline filled but does not initiate additional blood withdrawaÃs. In the case of microemboli detection, the system has effectively managed the patent#otiy dangerotis situation arict the nurse eeri ne notified to examine the system for emboli formation centers such as poorly fitting catheter junctions.
j00441 Example embodiment comprisitig a blood toop system with a peristaltic pump.
Figure 4 is a schematio iÃitistretion of a blood loop system with a peristaltic pump. The system of i~igure 4 is similar to that of Figure 3, with the syringe pump of Figzure 3 reptaced by a pedstattic ptirnp (51) atid a tubing reservoir (52). The reservoir as used in this application is defined as any device that allows for the storage of ttuid. Examples included are a piece of tubing, a coil of tuiaing, a bag, a tlexibte pillow, a syringr;, a bellows device, or any rievice that cac be expanded through pressure, a ttuid coIÃÃrrÃn, etc. The operation of the systeEn is esseiitiaily utichaiigect except for variations that reflect the change from a syringe pump to a peristattiG or ot.her type of pump. The blood loss and saline consumption requtreroer3ts of the system are of course differeiit due to tne blood saline interface present in the operation of the secorÃti peristaltic pump. Unlike the syrirtge pump of i"'igÃsre 3, the example embodiment of Figure 4 must maintain a sterile compartment and minimize the contact between air and blood for many applications. A
saline fluid column cafi fill the tubing, and effectively moves up and down as fluid is with drawn by the peristaitic pump, [00451 Push Pull System.
Figure 13 is a schematic illustration of a blood amess system according to the present invention. The system compcises a catheter (or sÃrnitar b#ood access devÃce) (12) in fluid communication -,vith the vascular system of a patient. A tubing extension (if required) extends from the catheter (12) to a junction (13). A first side of thp junction (13) connects with fttiict transport apparatfÃs (2) such as tubing (for reference purposes called the "ief''=k side" of the blood systerrÃ); a second side ofthe)unctior# (13) connects with fiuid transport apparatÃÃs (9) such as tubing (far reference pu rpases called the Yr#ght side" of the blood syst.erÃÃ). A sensor (1) is in fluid communication with the left side (2) of the system. A pump (3) is in fluid communication with the left side (2) of the system (shown in the figure as cfEstat frorn the patient relative to the sensor (1); the relative positions can be reversed),. A source (4) of suitable flt#irt sÃÃch as saline is ir) ftuid communication with the left side (2) of the s.ystern, A
waste cos3tainer (18) or connection to a waste channet is in fluid communication with the right side (9) of the system. In operation, the pump (3) operates to draw blood from the patient through the catheter (12) and junction (13) into the left side (2) of the system. The sensor 0) determines a desired property of the bioodf e.g., the glucose concentration in the blood. The pump (3) operates to draw saline from the container (4) and push the blood back into the patient through junction 0 3) and catheter (12). After a sufficient quantity of blood has been reinfused (e.g., hy volume, or by acceptable blood/saline mixing threshold), then the pump (3) operates to push remaining blood, htoodlsaiine mix, or salir}e into the right side (9) of the $ysteÃn and iÃito the waste cotitainer (18) or channel. The trarisport of fluid from the left side (2) to the 'right side (S) of the system can be used to clear undesirable fiuids (e.g., blood/saline mixtures that are jiot suitahle for reinfusion or measurement) and to flush the system to help in future measurement accuracy. Valves, pumps, or additional flow control devices can be used to control whether fluid from the left side (2) is inftised into the patient ortransported to the right side (9) of the system:;
and to prevent fluid from the right side (9) of the system from contamiEiating blood beiÃig withdrawn into the left side (2) of the system for measurement.
(00461 Push Putt System with Two Peri;staitic Pumps.
Figure 5 is a schematic illustration of abIoOd access system implemented based tipon a puiE-push mechanism with a second circuit provided to prevent fluid overioad of the patient. The system comprises a catheter (or similar blood access device) (12) in fluid communication w#h the vasctilar sysfern of a patient. A tubing extension (11) (if required) extends from the catheter (12) to a junction (13). A first side of the jtÃnction (13) connects with fluid transport apparatus (8) stach as tubing (for reference purpnses called the "teft side" of the blood loop); a second side of the jÃsr}ction (13) connects with fluid transport apparatus (9) such as tubing (for reference pairposes cailed the "right side"
of the bi:0art loop). An air detector (15) that can serve as a leak detector, a pressure measurern.eii#
device (17), a glucose sensor (2), and a needie-less blood access port (20) rnount with the left side af#he blood loop. A tubing reservoir (16) mounts with the left side of the blood loop, and is in #luid?
communication with a blood piirnp (t). Blood pump (1) is tn fltild communication with a re.sesvair s;183 of fluid suctr as saline. A blood leak detector (19) serves as a safety that can serve as aÃeak detector mounts with the right side of the blood ioop. A second bivcd pump (3) mounts with the right side of the blood loop, and is in fluid communication with a receptacle or channel for waste, depicted in the figure as a bag (4). Elements of the system at-td their operation are further described betav+s.
[00471 Blood sam ie and measurement process - First sample draw.
I , Pump (1) initiates a draw of blood from the catheter (12).
2. The blood interacts with the sensor measwrernent cell (2). The volume of the catheter (12) and tubing (11) can be determined and used fer future refprenee and for the determination of btaort-saiine mixing.
3. Sensor measurements can be made as the blood moves through the measurement cet1.
4. Pump (1) changes direction and sensor measurerneats. continue.
5. Pump (1) reinfuses blood into the patient. As the Ãrrlxed btood-saltne junction passes the ;tÃnction (13), it becomes progressively more dilute.
6. Following re-infusion or-the majority of the blood, peristaitic pump (3) is turned on and the saline with a small amount of residual blood is taken to the waste bag (4).
7. The system cart be washed with saline after each measurement if desired.
3. Additionally th:e system can go into an agitation mode that fully washes the system 9. Finally the system can enter into a keep vein open r.-nccie (K!/O). ln this mode a small arrtount of saline is continuously or periodically i3zfused to keep the blood access poir3t open.

10~348] Btood sam le and rneaseremeni rocess - Subse uent: Blood Sam Ãin , i arsubseqnent samples, the tubing between the patient and the pump (1) is filled with saline and it can be desirabJe that this saline not become Enixed with the blood. This can be achieved with operation as ftsilows:
I . Pump (1) irlitiates the blood draw by drawing blood upthroughjur~cticn{13}.
2. The withdrawal continues as blood passes through the sensor measurement cell (2). The blood after passi,ig the measurement cell can be effectively stored in the tubing reservoir (5).
3. Sensor measurements can be made during this withdrawal pericd.
4. FolÃowiEig completion of the blood withdrawal, the blood can be re-infused Into the patient by reversing the direction of pump (1).
5. Sensor measurements can also be made during the re-infusion perirad.
5. As the mixed blood-saline passes through the junction (13), it becomes progressively more dilute.
7. Following re-infusian of the majority of the blood, per#staltfc pump (3) is turned on at arate that matches the rate of pump (1). The small amount of residual bitiod mixed with the saline is taken to the waste bag (4), 8. This process results in a washing of the system with saline..

9. Add"Ãtional system cleaning is possible throtigh an agitation mode. In this morte the fituict is moved forward and back such that turbulence in the tiow occurs.
10. Be#weert blood samplings, the system can be placed in a keep vein open mode (KVC3). ir3 this mode a srrtalt amourÃt of saline can be iritused to keep the blood access point open.
[00491 Characteristics of Push Pull with Peristaltic Purr: s. The exen'rple embodiment of Figure 5 casi operate with minimal blood loss since the majorfty of the blood removed can be retumed to the patient. The diversion of saline into a waste channel can prevent the Infusion of significant amounts of saline into the patient. The pump can be used to compensate for different sizes of catheters. The system can detect partial or complete occlusion with either the analyte sensor or use of pressure sensor (17) or additional pressure sensors not shown. An occlusion can be cleared through a variety of means. For example If the vein is ccUpsing and the syst.em needs to re-infuse saiÃ#ie either the blood pump orthe flush pump can be t.tsed to effectively refill the vein. If there is evidesice of occlusion in the measurement cell area, the both the, blood pr.rrnp and flush pumps can be activated such that significant fluid can be flushed through the system for effective cleaning. In addition to high flow rates the bidirectional pump capabilities afthe pumps can be used to r-errrove occltasinns. If a microerrsboltis is detected the system can initiate a mode of operation such that the problematic blood is taken directly to waste. The system can then enter into a mode such that it becomes saline ttted but does not initia#e additional blood withdrawais. In the case of microemboli detection, the system has effectively managed the potentially dangertrus situation and the nurse can be notified to examine the system for emtaoti for-matiorl cas3tet-s such as poorty fitting catheter junctlons.
[00501 Push Pct[i System with Syringe Pump.
Figure 6 is a schematic illustration of a blood access system based tipon a pull-push mechanism with a second circuit provided to prevent fluid overload of the patiertt. The system comprises a catheter (or similar blood access device) (12) in fluid carnrrtiunication with the vascular system of a patient. A tubing extension (11) (if required) extends from the catheter (12) to a junction (13). A t'i:rst side o#the juriction (13) connects with t#ulct transpor! apparatus {8} s.uch as tubing (for reference purposes called the "left side" of the blood loop); a second side of the juryction (13) connects with fluid trarisparl: apparatus (9) such as tubing (for reforerrce purposes called the "right side" ot the blood loop). An air detector (15) that can serve as a tealc deteetor, a pressure measurement devlce (17), and a glucose sensor (1) mount bvÃth the leit side of the blood loop. A pinch valve (42) mounts between the left side (2) of the blood loop and a junction (40), controlling fluid communication therebetween. A. pinch valve (41) mounts between the 3unction (40) at7d a waste charineà (4) (such as abag)< controlling fluid cgmmuritcatiori therebetween. A
pinch valve (43) mounts between. the junction (40) and a source of wash fluid (18) (SSactr as a bag of saline), controlling fluid flow there between. A syringe pump (5) mounts in fluid commcrrricatiorr with the junction (40). Ablofld leak detector {'lP} that can serve as a leak detector mounts with the right side afthe blood loop. A second blood pump (6) mounts with the right side of the blood laop, and is in fluid communication with a receptacle or channel for waste, dep3cted in the figr.ire as a bag (4). Elements of the system and their operation are further described below.
ti1t1s1l Blnosl sarrr Ie and rneastarerxrent rocess -~Ãrst sarn 9e draw.
'Ã. Syringe pump (5) initiates a draw.

2. The blood interacts with the sensor measurement cell (1). The voitime nfthe catheter (12) and tubing (11) can be determined and used for future refere ce and for the determination of biaod-saiine mixing, 3. Sensor measurements can be made as the blood moves through the measurement ce11.
4. The syriilge pump changes direction and sertsor rneasure:ments can contirtue.
5. Blood is re infused into the patient. As the mixed blood-saline junction passes the junction ('f q)> #t becomes progressively more dilute.
6. Following re~infusion of a portion the majority) of the bload: peristaitic pump (6) is turned on and the saline with a small amount of residual blood is taken to the waste bag.
7. The system can be washed with saline after each rrteasurea-erit if desired.
8, Aciditiorraliy the system can go into an agitatian mode that firtly washes the system.
9. Finally the system can enter a keep vein. Qpera. mcfe (KVO). !n this mode a small amount of saline is infused to keep the blood access point open.
[0~162] Blood sample and measurement process - Subse Lient Blood Sam i#n ,Fcr subsequent samples, the tt#bing between the patient anr} the syringe is filled saline and it can be desirable that this sa[irte not become mixed with the biood. The pinch valves enable the saline to be pushed to waste and the amount of satine;bfood mixing to be minimized. This can be achieved with operation as described below.
t. Syringe pump (5) initiates the blood ciraw by c#rawing blood up thrvugh junction (13).
2. The withdrawal contirtties tintil blood saline jurscttire reaches the base of the syrir#ge. At this point in the sequence, pinch valve (42) is closed aEict v~aiue (41) is op-erYed, arici the syringe pump direction reversed. This process enables the resident saline to be placed into the waste bag.
3. Valve (42) is opened, vatve (41) closed and the syringe is now withdrawn so that only blood or blood with very iittte saline c.drttarrtin,atidn is pulled into the syririge.
4. Sensor rneasuret-nents caii be made cturitig this witi7drawat period.
5. Following completion otthe blood withdrawal, the blood is re-infused into the patient by reveEsing the direction of the syrtnge purnp. As the mixed blood-saline passed through the junction (9 S), it becomes progressively more dlltlte.
6. Following re-infusion ofthe majcrity of the bioed, perisffaitic pump (p) is activated with the concurretit iiifusion from the syringe pUrnp and the saline with a small amount of residual blood it taken to the waste bag.
7. This process results in a washing of the system with salisie.
8. Additional system cleaning is possible through an agitation rnor3e. In this mode the fluid is moved forward and back such that ttFrbuience in the Ocvs occurs.
9. Between blood samplings, the system can be placed in a keep vein open mode (KVO). In this mode a small amount of saline is infused to keep the blood access paiiit open.
.[0063] Characteristics of r;'ush Ptil3 with Syrincte PttrniL The system can cperate with little blood loss since the rr-a}nrity of blood is re-infused into the patient. The diversion of saline to waste can result in very little saline infused into the patient. Saline mixing occurs only during blood inftrsion. The pressure monitor can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pilii and push of the blood access system. The system can compensate for different size catheters through the volume pulled via the syritige pump.
10054) The systern can detect partial or complete occlusion with eitherfhe arialyto sensor or the pressure sensor. An oce[usÃon can be cleared through a variety of meaus. For example if#he veirl is collapsing and the system needs to re-infuse saline either the syringe plFmp ortht, filEsh plFmp oat3 he used to effectively refill the vein. If there is evidence of occlusion in the measurement cell area, both the syringe pump and flush pumps can be ae#ivated such that significant fluid can be flushed through the system for effeotive cleaning. Inadditipn to high flow rates the bidirectional pump capabilities of the pumps can be used to remove occlusions.
j00561 The syriiyge pump mechanism can also have a source of heparin or other anticoayutalit attached thÃough an additional port (not shown). The anticoagulant solution can then be drawn intv the syringe and infused into the patient or pciiled through the flush side of the system. The ability to rinse the systern with such a solution can be advantageous when any type of occlusion is detected.
[0066] If a microembolus is detected the system can initiate a mode of operation such that ihe problematic blood is Y.aken directky to waste. The system can then enter into a mode slioh that it becomes saline filed but does not initiate additional blood withdrawals. In th-e case of microemboli detection, the system has effectively managed the potentially dangerolis siÃliation and the nurse oan be notified to examine the system for emboli formation centers slich as pooety fitting catheter jtinations.
[00571 Push Pull SystetTt with Syritige & Peristaltic Pump.
Figure 7 is a sohematio ikilÃsfir,ation of another example push pull system.
Th-e system cornprises a catheter (or similar blood access device) (12) in fluid communication with the vascular system of a patient. A tubing extension (11) (if required) extends from the catheter (14) to a junction (1~3). A first side of the junction (10) tx~nriects with fluid transpart. apparatus (8) such as tubing (far reference purposes called the "left side" of the blood Icsop)< a second side of the junction (10) connects with fluid transport apparatus (9) such as tubing (for refereioe purposes called the "ri.ght side"
of tt3e bÃood toop). An air ciefeotor (15) that can serve as a leak detector, a pressure measurement device (17), and a glucose sensor (i) mouitt with the left side of the blood loop. A blood pump (2) mounts with the left side of the blood loop slsO. that it controls flow between a passive reservoir (5) antt t.tie left side of the blood loop. A
pinch valve (45) mounts with the right side of the blood loop, controliiag flow between the right side of the blood loop and a second pump (4). The second pump (4) Is also in fluid communication with a waste channel such as a bag (20), with a leak detector (19) mounted between the pump (4) and the bag (20)..A
pinch valve (41) f-naunts between the pump (4) and a port of the passive reservoir (5), which port is also in #tltid communication with a pinci'- valve (43) between the port and a source of.salÃne such as a bag (18), Eiements afthe system and their operation a1'e further desoribed: iaeiow.
[00681 H1ood sam Ie and rneasurement rocess - Sam lin rocess.
t. The passive reservoir is not filled and valve (41) is open.
~. Peristaific pump (4) & pump (2) initiate the blood draw. The saiine in the line moves into the saline bag.
3. As the blood approaches the syringe, pump (4) stops and valve (41) cioses.
The blood now moves into the passive reservoir.

4, Sensor sarrtfslitYci of the blood occurs in sensor (1).
5. Pump (2) reverses direction and the blood is iaifused into the patierit.
e. The reservoir goes to minimum volurne, at which point valve (43) opens and saÃine washes the t'esetvoir and is Us.ed to push the blood back to the patient.
7. As the mixed biooct-saiinr passes thratagh the jurtctiort (13), it, becomes progressively more dilute, S. FallQwing rce-irtfusioEi of the majority of the blood or all ofttte blood, Wistattic pump (4) is turned on at the same rate as pump (2) and valves (45) and (43) are open. The coÃnbirtaÃiati of pumps creates a wash circuit that cleans the system.
9. Furtherwasi'tirig of the syringe reservoircan occur by opening valves (43, 41) with pump (4) actlve.
10. Keep vein open infcasiatis can occur by having pump (2) active with valve (43) :cpen.
[0058] Charar.t.eristics of the Push Puli 5 stern witb $rin e and Per'r,staEti~ . Blood is always moving either into or out of the access system. Circctit cleaning can be independent ofsyringe cteaatng.
Blood loss is zero or minimal since the majority of blood is re-infused in to the patient. Very little saline is infused due to diversion ot'saline iiito waste and the fact that the mixing period is only during infusion.
Saline mixing diar#ng blood infusion only. The system contains a pressure rrtcrnitor that can provide arterial, central versous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access systein_ The system can compensate for difrererii size catheters through the volume pulled via the syringe ptimp.
[0E160] The system can detect partial or complete occlusion with either the artaiyte sensor or the pressure sensor.. An or.ciirsion can be cleared through a variety of means.
For example if the vein is collapsing and the system needs to re-infuse satine via either syringe prtrnp.
If there is evidence of occlusion in the measurement cell area, the both syringe pumps can be activated such that significant fluid cat-i be flushed through the syste-n far effective cleaning. In addition to high fiow rates the bidirectional pump capabilities of the: pumps can be used to remove occiusinns. The flexibility of the described system w#th the various pinch valves allows one to identify the occlusion locatiati and establish a proactive cleaning pragram to minimize further occlusion.
[00811 The syringe pump mechanism can also have a sot:.roe of heparin or other anticoagulant attached through an additional port (not shown). The anticcsagulasit solution can then be draoiti into the syringe and infused into the patient ar, pulled through the flush side of the system. The ability to rinse the systetrt m+s+ith such a solution could be advatitageous when any type of occlusion is detected.
[0062] Push Pull System.
Figure 14 is a schematic illustration of a blood access system according to the present Ãtiventiort. The system comprises a catheter (or similar blood access device) (12) in fluid communication with the vascular system of a patient. A tiabirtg extertsion (if reqttlred) extends from the catheter (12) to a junction (I $). A first side of the junotion 03} connects witb fluid traiisport apparatus (2) such as tubing (for reference purposes called the "left sicle" of the blood systern); a second side of the jtjnction (13) connects with fluid transport apparatus (9) such as ttibirtg (for reference purposes called the right side" of the blood system). A pump (3) is in fluid cornmun'ication with the left side (2) of the syst.em. A source (4) of suitable fitiid such as saline is in fitjicf communication with the left side (2) oÃthe system. A sensor (1) is in fluid cÃat-omunicatior~ with the right side (9) of the system. A waste cot7tainer (18) or connection to a waste channel is In fluid communication with the right side (9) ot'the system. An optional fiuÃti trarisport apparatus 22 is in fluid communication with the right side (9) of the system between the sensor (1) arid the waste container (IS) or ctZennei, and with #he: taaiient via th r=, catheter [0063] In operation, the pump (3) operates to draw blood from the patient through'the catheter (12) a.ncÃ,junction (13) into the left side (2) ofth-e system. Once a sufÃicEent volume of blood has been drawn into the left side (2), the pump operates to push the blood from the left side (2) to the right side (9), wherein the sensor (1) determines a desir~ed blood property (e.g., the cxxrÃcer#traÃion of glucose in the blood). The pump (3) cari draw saline frtai-n the bag (4) to push the blood through the system. 8tood from the sensor (1) can be pushed to the waste contaitier (16) or channel, or can optionally W. rettirnecà to the patient Vfa the optional return paii? (22). The transport of fic1id through from the left side (2) to the right side (1~) of the systern car} be tÃsed to clear tir}desirabte Ãtijiris (e.g., blood/saline mbdures that are not suitabie for reinfusion or measurement) and to flush The system to help in Ãixture meastiremer#t accuracy.
Valves, pumps, or ,es4ditiortal flow control devices can be used to control whether fluid is drawn from patient into the left side (2) or transported to the right side (9) of the system, and to prevcnt. blood/saline m%x and saline frorrr the leÃt, sirie (9) of the system from being inftÃsed Into the patient..
(00641 Push Pull with A+dditionat Path.
Figum 24 is a schernatic iÃtustra'tirsn of an exar-npte emboelir-nent. The sys.tern cornprises a catheter {r,r similar blood access dev#ce} (12) in fttÃiri communication with the vascular system of apat#ent, and in fluid communication with ajrancticzrE (13). A first side of the junction (13) connects with fluid transport apparatus (8) such as t.EÃbing (for reference purposes called the uleft side"
of the system), The left side of the system futther comprises a source of maintenance #tuirà (18) and a con-iectioti to ot7e side of aVoenr through glucose se#fsor system Ã9y. A first fluid corifmi system, ~ t }
controls fluid flow wfthÃr3 the left side of the system. A secoiid side of the junction (13) cannects with fluid transpctrt apparatus (7) such as tubing (for reforence purposes called the "rÃght side" of the system). The right side of t.tte system further comprises a channel or receptacle for waste (4), and a connectirsn to a second side of the fiow through glucose sensor system (9). A second fluid control system (2) controls fluid flow within the teft side of tile system. In operation, the first and soooncJ: fluid control systems are operated to draw blood from the patient to the junction (13), and then ft7to either the left or right side of the system. The fluid control system can then be operated to flow at. least a portion of the blood to the glucose measurement systein (9), where the glucose concentratioii of the blood (or other aiia[yte prrrperty, W another analyte sensor is employed) can. be dotermined. The fluid control systems can then be operated to flow the blood, including at least aportÃon of the blood measured by the giucase measurement system. #t3to either the left or right side of the system and then back to the patient. As desired, the fluid control systems can be operated to flow maintenance fluicE from the maintenance fluid source {'Ã 8}
throLigh the glucose measurement system (9) to the waste channel (4) to faciÃitate cteaning or calibration o#'thc system. The tt ir3 control systems can also be operated to flow maintenance fluid through the left and rfght sides to facilitate cleaning of the tubing or other tltxid transport mechanisrns. The fluid control systems can also be operated to flow maÃr~tenarsce fluid into tt~r: pafie~tt, for example at a low rate to maintain csppn access to the circulatory system of the patient.
100651 Push Pull With Addittonat Path.
Figure 8 is a scherr~atic illustration af a~i example embodÃment. The system comprises a cathete'r (or ,%imi#arbiood accr-.ss device) (12) in ttuid co~r~rsur}ication with the vascular syst.enn of'a faatie;r~t. A tubirig exiertsion (11) (if required) extends from the catheter (12) to a junction (13). A first side of the junction (13) connects with ftuid transport apparatus ($) such as tubing (for reference purposes catteci the uteft sideN ofi the blood Ioop); a second side of the junction (13) connects vaith fluid transport apparatus (7) such as tubing (for reference purposes called the "right sids" of the blood loop). A pinch valve (44) cta~itrols flow between the left side (8) of the blorsd loop and an intermediate fluid section (6). A pump (1) mounts between the Inter~n~diate WiÃd section (6) and a sociroe of salÃne stach as a ba9 {IS}. A taislch valve (43) cantroÃs ftow between the right side (7) of the blood loop and an EntermedÃate f7uitt sectican (5).
A pump (2) rnotirsts between the intermediate -fluiri section (5) and a waste channel such as a bag {eÃ}. A
glucose sensor (9) mounts between the two intermediate flLiid sections (6, 5).
Elements and their operation are fudher described below.
[0068) Siood samote and m.easure~t pracess.
I . Blood is removed from the patient via the blood pump (1) whÃle pinch valve (44) is open and pinch valve (43) is closed.
Z At the e~zd ot'the draw blood is diverted into the tubing patÃi coriteir~ir~g the measumnier~t cell (9) by activation of pump (2) with the concurrent closure of pÃnch vaive (43).
3. A volume of blood appropriate for the Eneasurernent can be pulled into (or past as needed) 91LIcose sensor (9) and into tubing (5). The rate at which the blood Ãs pulled into tubing (5) can be performed such that the dr-aw time is mir~irnixed.
4. At this juncture the re-Int'usÃosi pracess can be ir~itiated. Pump (2) initÃates a re-infusion caf'the blood at a rate cGfzsisient with the measurement of the btood sample. In general tert-as this rate is slow as the blood simply needs to flow at a i-ate that results iri a substantially constant sensor sampling.
Concurrently, puf-np (1) initiates a re-infusion of the blood.
5. As has been described previously, the amount of saline infused into the patient can be controlled via the use of the flush line (7).
6. The system can then be completely cteaned via the use of the two pumps (1, 2~ as wetl as pinch valves (43, 44).
[00671 Qharaoteristics of Push Pult with At3ditional Path. This example embodiment can perforrn rneasurement and infusion concurrently. In the previously-descrihed ptfsh-pti(Ã system the withdrawai, measure~nent,. and reg-infusion generally occur in a sequential manner. In the system of FigLtre 8 the measurement process can be done in parallel with the ir~ftjsior~. The reduction in overall cycle time can be approximately 30%.
(00681 In addition to the redt~ctien in total cycie time, the system has the ability to provide iiicfependeni cleaning paths. By closing or opening the pinch valves in combination with the txvo pumps, the system can create bi-directional flows and clean the sensor measurement cell independent of the rest of the circEiit. Such independent cleaning paths are especially useful when managing ett.hercr,t'rsptete or partiai occlusiolis.
[00631 The push pull with additional path system as illustrated In Figure 8 is an exampte embodiment of otie possible configuration. T" pump rnecha-iism can be moved to the portion of tubing between the junction leading to the giticose sensor and tbe patieizt. Many other pump ai3d flow cantrol devices can be used to create the operational objectives defined abave.
Additionally, the system can be realized with only one pump.
[00701 The push pull with additi.onal path system as ilitistrated in Figure 8 also has the advantage of being able to deliver a sample to the glucose sensor without it being preceded by saline. As the blood is withdrawn up the left side of the circuit the saiine/blooci transition area +Ca{i be moved beyond the location where blood sensor (9) connects with tt;bir-g (B), At this point, the blood that Ãs ;r*ved into sensor (9) could have a very small or no leading saline boundary, The lack of such a leading saline boundary can facilitate the use afthe system with existing bi:t7ott giticose meters.
Typically, these meters make the assumption that all fluid in cont-act with the disposal strip is blood, not a rn#xtt,ire of blood and saiÃne, [0071] Sample tsotation at the Arm with Subsequent Ã3Ãscard.
Figt.ire 9 is a schematic; iiiustration of an example embodiment that allows a blood sample for rneasurerneat to be isolated at a point near the patient and then transported to the instrFimeot for measurement. The system shown does not require electronic systems attached to the patient. A
ilydraulicatiy actuated syringe (10) is providect, with a pump (1) and salÃne reservoir (11) and tubing (12) provided to control actt#ation of the syringe (10). A catheter (12) is in -ff cid ccrrnmtsr#'icetioti with the vascular system of a patient. The syringe (10) can mount such that it draws blood from the patient via the catheter {12}. A valve (4) controls flow between the catheter and a transport mechanism (5) in fluid communication with a glucose rneasuremetit device (6). The syringe (10) is also in fluid communication iVtth a pump (7) and an associated fluid reservoir such as a bag of saiitle (8). The system oan be described as one that is remotely activated by hydraulic action. Elements of the system and their operation are further described below.
tt#O721 Blood sample and measurement process.
I . The blood Is w,thdm, wtt from the patient using hydraulically activated syringe (1). The syringe is controlled by pump (1).
2. The removal of some blood into syringe (2) creates an utidiictted and clean blood sample in catheter (3)..
3. Valve (4) is activated ij7tc;' an open positiesi such ti1aY e small sample of blood is diverted into tttbing pathway {5}. The blood is subsequently transported to measurement cell (6) for measurement. The blood iransport. into glucose sensor (6) can be via air, saline or other appropriate substances.
4. The blood in syringe (2) is re-infused by activation of pump (1). Following reyinfusion of the blood ihe system can be cleaned with saliite by activation of pump (7).
5. The blood located in the measurement ceii is measured and subseqr.tentiy discarded to waste (not shown).
[00731 The system can be operated in several different mocies. The delivery of a small sample to the measurement site can be easily accomplished by the use of air gaps to isolate the sample from other fJtsids that can othertivise ter:d to di#tate the sample. In fhi.s MeasuM.rnent method ihr volume of the sarnple, does tiot need to be tightly contratÃed arid the measurement system measures the glucose (mg/di) in the sensor Gelt, 100741 An, alternative approach iiivolves either reproducible cotitrol of the volcime of blood or determination of the vol[zrne of blood and integration ofthe total arnaant. of gliAcose measured, as illustrated in Figure 10, The blood sample can then underqo significant mixing with the translao rt fluids sit7ce there is no requirement that an undiluted sample be delivered to the setisor c;ell. The system can effectively cÃetermine the total amount of glucose measured. The total amount of glucose could be determined by a simple integratioti for the area under the curve. With both ttie total amount fgluctase known and the volume of blood pracessed, an accurate determi{iatirs-i afthe blood gluccse cati be niade.
[o'75) Ct~aracteristics t~f Sarr7 le Isolation at the Arrn with Subse uer~t l~iscar~, The total amoarft of blood removed during the sampling process is minimized by this system.
Additionally the amount of saline infusect is also minimized.
[0076] The pressure needed to withdrawal the blood sarrrple can be monitored for partial or complete acclusion. If such a situation is observed the flush purnp can be used to either clean the catheter or to clean the circuit over to the measurement cell. In addition the activation of the flush pe.Ãmp ÃrF
conjunction with the hydraulic syringe can be used to create rapid flows, tc#cbulent flows and to isolate particular components of the circuit for cleaning.
[0077] Sanipte tsvtation system.
Figure 15 is a schernatic illiisttafiioti of a blood access system according to the present invention. The system comprises a catheter (or similar irrfocad access device) {12} in fÃuid tomrnunication with the vascular system of a patient. A tubing extension (51) (if required) extends from the catheter {12} to a junction (13). A first side of the junction (13) cont}ects with. fluid transport apparatus (52) such as iub#ng; a second side of the junction (13) cGnnect.s with fluid transport apparatus (53) such as tcibing. A sample systein (38) is iti fluid communication with fluid transport apparatus (52).
Aoize-way fluid control device (32) a ctteck ualve} recetves tonnects so as to receive ttuizt from fluid transport apparatus (53) ar3d deliver to a junction (33). A#irst side of tbe;urtctitrti (3,S) is in fluid communication with a dtive system (39); a second side of the junction is in fluid communication with fluid transport apparatus (54) sueh as tubing. A sensor (49) is connected so as to receive fluid frÃtrn fluid transport apparatus (54). A waste coiitainer or chasine[ (46) is connected so as to receive tlciid from the sensor (49). (53), (32) and (33) can be separate components or be integrated as a single. cornponent to minimize dead space volume between the functions of eachcamponent.
100781 In operation, the sample system (38) draws blood from the patient into #ltiid transport apparatus (51) and (52). After a sufflcient volume of blood has been drawn into (51) and (A2), the sample system (38) pi,shed blood from (52)through one-way device (32) tQjunction (33). Drive system (39) ptasftes a'plug:' into junction (33), where a plug can comprise a quantity of a substance relatively immiscible with blood and suitable for transport thrctigh tubing or other components in transport apparatus (54) and suitable for transport tE3rougl't sensor (49) wÃft3out contamination of the sensor r49}.
Examples of stiitable plug materials include air, inert gases, polyethylene gtycol (PEG), or other similar materials. An alternative type of pitiq can comprise fixing or clotting the blood at the leading and trailing edges. Specifirally, glutaratdehycte is a:substance that caÃÃses the hemoglobin in the red blood cell to become gelatinous. The net resLÃit is a gelatinous plug that cari be used effectively to separate the blood used for measurement froÃ-n the surrounding fluid. After the initial plug is pushed into junction (33), sample system (38) pushes additiQnat fluid into (52), forcing blood from (63) past junction (33) fQrcirtgthe initial plug in front ofthr-, blood into transpott afspat-atus (54). Sampte ;iystem can push blood into (52); or can push another suitable fluid such as saline into (52), or can redÃ.tce the volume of (52), or any other method that moves the blood in (B) iEitcr junction (33) aiid transport apparatus (54). Once a suft'Ãcient ttuant.ity of blood is present in transport apparatus (54), drive system (39) can pusi? a secesrteà csrtrailiiig plug into junction (33). Transport system (39) can then push the plug-blood-plug packet through transport apparatus (54) scà that the blood caEi be measui-ect by sensor (49). The blood can be immediately pushed to waste (45), or pushed to waste by the transport of a subsertÃ,fent 5ample.
Sance the blood #11 transportr apparatus (54) Ãs surrounded by relatively Immiscible plugs, and since the drive system (39) caÃi push the plug-blood-plug paoket using techniques optimized for transport (e.g.;
pressurized air or other gas, or mechanical compression of transport apparatLis (54)), the blood can be transported more quickly, and over greater distances, than if the patient's blood or saline were used as the motive rr}editÃm.
E00791 Sample 1sotatiori though Use of Air Gaps.
i"icttÃre 'i'[ is a schematic iiitÃstratlor} of an example embodiment that allows a blood sample for measurement to be isoiated at a point rrearthe patierÃt aÃtd then transported to the i:nstrcÃment for measurement through the use of leading and ttte -iollawir}g air gaps. The system is able to effectively introduce air gaps through a seri-es of one-way valves while concurrerÃtfy preventing airfroÃxs being infused into the patient. The system is adapted to connect with the circuiat.iorà system of apatient through blood access device (50). A recirculating junction (31) has a ftrst port in fluid communication with a patient, with: a second port in fluid communication with a oFie-wa.y (or check) valve (32). The valve (32) allows flow only away from the recirculatirig junction (31) toward a port of a seccÃr~d juncticÃrt (33). A
second port of the second junction (3S) is in fluid communication with a one-way valve (34), which allows flow only towards the s.ecarld junction (33). The one-vuay valve (34) is in ftuid comrnurtication with another one-way valve (35) and with aEi air pump (39). The ccÃrnmunication betweell the air pump (39) aiid the ona-way valve (35) can be protected with a pressure relief valve (40). The one-way valve (35) accepts air from an external source. A. third port cfthe second junction (33) is in fluid communication with a glucose sensor (49), which in ium Is in fluid communication with a pump {48), and then to a one-way valve (44) that allows flow from the pump to a waste ctÃ.annel such as a waste bag (45).
Another port of recirculating jurietion (31) is in fluid communication with apuanp (38). The path from the recirculating junction (~I) to the pump (38) can atso interface ovith a pressure sensor (37) and an air detector (36). The pump (38) is in f#uÃd communication with a jundion (4~). Another port ofjuncticn (42) is in fluid communica.tion with a one-way valve (43) that allows fluid flow from the pump (38) to a waste channel such as waste bag (45).
Another port of junction (42) is in fluid commÃinicat.ion with a one-way valve (47) that atlows filuicà flow from a saline source such as sal"Ãne bag (46) to the pump (38). Manual pincholamps and access ports can be provicÃoci at various locations to allow disconnection and access, e.g., to allow disconnection from the patient.

j130801 Btgod.saoptt ~~r3.rne~st~rrsrt~ f-fi.prr~c~s~:
1. BIooQ is withdrawfi from the patient utilizing the blood pump uritil a clean or uncontaminated sample has been pulled pass the recir4ru[ation junction.
Z. AcÃdItional blood is WithdraWn frorn the patient by activatior~ offhe pump labeled rectrcutatiQn pump. Blood is pulled to the air junctirarz.
3. An air plug is created by pulling back on the air pump (39). The or#e lay valve -at the air intake allows air into the tubing set for the formation of asrnall air gap.
4. The air gap is infused thror~gb, valve (34) to create a leading air gap in Juriotian(,33) which is located at the leadit-ig edge of the uncontaminated blood sample.
5. The rE;circulation purnp (48) then withdraws blood fro{n the patient until an appropriate volume of uncontaminated blood has been procured.
6. The air pump (39) is agaiEi operated in the n-odo to create a secotid air gap that will be used as a traiting aÃ'r segment.
7. The second air plug is ir<fuseri through valve (34) to create a following air gap, 8. The blood residing in the line leading to the blood pump is Ãrtf~~ise'd into the patient.
9. The blood sample with leading and trailing air gaps is now transported over to the glucose sensor (45).. Once tn contact with the glucose sensor, an accurate glucose -measurerneni can be made.
M Following completion of the rneastarerr#ent sample is discarded to waste (45).

11. The crrc.ult is now coEnpletely filled with saline and addWionat cleaning the circuit can be pe rforrrrect.
[i}ttsil Characteristics of'saEn te isolation by leading anct trailins air a s. There are a number of advantages associated with this isolation 5ystern, specifically the total amount of blood removed fi-om the paiient can be significantly less due to the fact that the blood sample is isolated at a point very close to the patient. The isolation of the blood sample and transportation: of that small amount of blood to the measurement has advantages relative to a system that transports a large arnount of blood to the maasuromartt siÃe. The fact that a stnalt amourit of total blood is withdrawn results in decreased overall tttsasurement time or dwell time. The decreased amount of blood removed enables the system to operate at lower overalt withdrawal rat-es and with lowar pressures.
AdditionaÃty, the isolation the blood sample has the advantage at the isolated sampte can be measured for a prolonged period oftime? can be altered in ways that are incompatible with reinfusion into the patient. bue to pressure monitorilig: on the blao(t withdrawal and the possible inclusion of a second pressure sensor on the recirculation side of the circuit (not shown), the circuit desigi3 has extrer-nety good occlusioii nianagement oapahllitias. The isolation of the blood sample and inability to re-Ãnfuse the sample due to the use of one-way valves, can oraate the oppo{ lutiity to cise nrsr,-sterÃle measurement methodologies.
10082.1 Hematocrit influence on withdrawal ressures.
Figure 16 is an illustration of a relationship betveen wi#hdrawal presstare, tubing diameter and blood fraction at a fixed hematocrit. As used here blood fraOon is the percent volume occupied by blood assuming a 7 foot length uftubing. Figtire. 16 depicts this relationship assuming a hernatocrit of 25%.
Figure 17 is the same information but assuming a hernatocrit of 45QJa.
Examination of these graphs shows significant pressure increases associated with increasing hematocrit, decreasing tube size and increasing blood fraction. In general terrns, it can be desirable to lise smaller tubing as the amount of blood.required is less a31d the length of the blood saiicze juncfloa is less.
These generally desirable a.ttriblÃtes are offset by the fact that srrralier tubing requires higher plrrnp pressures. Coinparisorl of'figure 16 with figure 17 also shows that there is strong sensitivity to the fraction of blood and the tubing diameter. tVfth agIlrcose measurement methociotcxgy that rrquires only a smaii sample of blood, it can be desiraiaie to use a smaller blood fraction which results in lower overall circuit pressures.
E{3{1831 Liernatocrit iEifilÃence on blood satine 'uaction.
Figure 18 shows a test system used to determitie the amoutit of t3locd saline mWng that occurs during transport of the blood through the tubing, iÃ}ciuding the luer fitting5:
junctions, at7d the subsequent filling of the optical cuvette. In testing, the system is initially filled Wah saline and blood is withdrawn intrs the tubing set. An optical rnea.surefnent is performed throughout the withdrawal cycie. As the transition from saline to blood occtÃrs the optical density indicated by the optical measurement of the sample changes, A
transition volume representing the vcsllirne needed to progress from 5%
abscrrbance to,95~'fn absorbarsce can be calculated from the recorded data, Figure 19 shows the results from the above test apparatus fcsr-two hematocrit levels, 23~"e and 51 %. As can be seen from Iwiglrre 'E 9, the transition volLÃme is greater for the lower hematqcrit blood. The dependence of the transition vclEime an hematocrit level can be used as an operating parameter for improved blood circuit operation.
[00841 Use of btooÃt I saline trar-r.sifion for rrreasuremerrt redictions As shown in Figure 19, the transi'tion from saline to blood is a systematic and eÃ-epeatabie transition. By using the fact that the transition is repeatable for a given hematocrit, the rrreaslireÃrrerlt process can be initiated at the start of this transition zone. In the case of 23%
herrÃatocrtt, the lneasuremerit process could be initiated falling vuithdrawat of 1.5 ml. The measurement process could then accocrnt for the fact that there is a known dilution profile as a function ofwithdrawa.t amourrt.
For, example the system can make measurements at discrete intervals and project to the ooÃ-rect undiluted glucose concentration.
-tooas] Modified Operation of Push Pu115ystem wrtt'r "t'wn Peristattic Pumps.
Figure 20 is a scheÃnatic illustration of a blood aocess system based upon apush-puÃi mecbarr"rsm with a second circuit provided to prevent fluid overload in the patient. The circuit is similar to that depicted in Figure 5 but is operated in trlantzerthat optimizes sever.a.t operational pararneter.s. Tho system comprises a catheter (or similar blood aocess devi.ce) (12) in fluid communication with the vascularsyst.em of a patierit. A tubing extension (11) (if required) eAends from the catheter (12) to a Junctiorr (13). Affrst side of the junction (13) connects with fluid transport apparatus (8) sÃaGh as tubing (for reference purposes called the "ieft side" of the blood ioop)~ a secoi7d side of the junction (13) coiinects with fluid transport apparatus (9) such as tubing (for reference purposes called ttr.e "right sirie" of the blood ioep}. An air deteotor {16} ttiat can serve as a 1eak detector, -a pressure measurement device (17), ar}d a glucose sensor (2) mounted on the left side of the blood toof-. A tcÃbing reservoir (16) mounts with the left side of the blood loop, and is in fluid communication with a blood plrmp (1). Blood pLrmp (1) is in fluid communication with a reservoir (18) of fruid such as saiirÃe. A second air detector (19) that can serve as a leak detector mounts with the right side of the blo+nd loop. A ser.orid blood pump (3) mounts with the right side of the blood loop, and is in fitÃid communication with a receptacle crchannel forwaste, depicted in the figure as a bag (4). A second presslrre sensor (20) can mount with the right side of the blood loop. An additional element shown in Figiire 20 is the specific identification of an extension set. The 4exiension set is a small length of tubing used betwee the standard catheter and the blood access circuit. This extension set, adds additional dead volume and other jonctions that can be probtema#ic from cleaning perspective. Elements of the system and their operation are further described below.
100861 i;ltodificri o erat}ons. As shown in the prec~-Aing pi:ots, high hematocrit blood requires a large pressure gradient but the increasert viscosity of the blood resaits in srrraiter#fansition volumes. Lower herrt.atocrià blood is the opposite, req:uirfng lower pressures and iar:gertransition votumes: In simple terms, the device caix be operated to withdraw only enough bl.ood such that an undiluÃed sa.rnple can be tested by the glucose sensor. Due to the tower transition volumes associated with higher hematocrit blood the amount of blood dra3+vn can be appreciabiy smaller than the volume needed with lower hern.atoerit blood. For operation on a human subject the following general crEteria can be desirable:
1) Minimize the total amount of blood withdrawn, this towers overall exposure of blood to con-human sarFaces.
2) Minimize the maximum pressure needed fa.rcarithdrawal: this reduces the power requirements and pump sizes needed to move the blood.
q) Utilize the smallest tubing diameter possible, this reduces the blood voicirs-ie and reduces mixing at the b1oodlsaline interface.
4) Clean out the tubing between the blood vessel and the junction as soon as possible. this can help reduce the likelihood of clotting at this location.
j00871 Btooct sarn Ãe anct measarement rocess - Subse uent Btooct um .
The example circuit shoxnin in Figure 20 can be operated in the manner that balances the four Ãaofer3tiatty competing objectives set forth above. The system can achieve improved performance by taking advantage of the small amount of undiluted blood sample actuaEly required for sensor operation. Notice that, while a blood sample must be transported through the left side, the left side does not need to be completely filled with blood. Saline (or another suitable fluid or material) can be used to push a blood sample to the sensor. An example sequence of steps are set forth below:
I. Pump (1) initiates a blood draw by drawing blood through junction(i 3).
2. The withdrawal continues until enough bioori has been wittidrawn past ttie junction of junction (13) and the right si.de (9) of the loop such than an unctituted. and appropriately siZerà blood segment can be delivered to the glucose sensor, as illustrated schematically in i"igzire 21.As mentioned above the amount of blood needed can be hematocrit dependent. Therefore, Ãhe srnoont. of blood withdrawn past the juttction (13) can be controlled based on measured hematflcrit: s1-nalCer blood segments with higher hematocrit and larger blood segments with lower hematocdt. Following the withdrawal of an appropriate blood segment, the blood pump (1) continues to operate bcit the fttistr pump (3) is also turned on, as illustrated schematically in Figure 22. The flush pump (3) can be operated at a rate equivalent to or greater than the blood fstarrtp (1). If operated at a rate greater then the blood pump (1), the flow rate imbalance fvrces saiine (or other suitable fluid or rnaÃeriai} into the right side (a), transporting the blood sample segment to the sensor, and also back intc, the extc:nsion tubing (11), cleaning the jc4nction (13) and the extension tubing (11). As an example, the flush ptimp can inÃtiaiiy he actuated at very high rratP to rapidly clean the ttÃb-ng connected to the patient and then decreased to prirnariiy facilitate transport of the blood segtnent to the sensor measurernent site.
3. As blood passes through the seR7sor measurement cell (2), it is stored in the tubing reservoir (16).
4. Sensor measurements cart be made duritig this withdrawat period.
5. The blood can be moved back and forth overthe: sonsor for an inoreastÃd rneastÃremc:33t pet-Formance (in some sensor embodiments) without the requirement for greater blood volumes.
4. Following completion of the blood meastaretnerÃt, the blood cati be re-infused into the patierA by reversing the direction of pump (1).
5. Sensor measurements can also be made during the re-infusion period.
& As the mixed bioad=saiine passes thresugft the junof#on<13}, it becomes progressively more di[ute.
7, Following re-infusion o.f the majority of the biood, flush pump (3) is turned on at a rate equal to or less than the rate of pump {1}. If less than the rate of pump (1) then there is a small amoutit of saiine re-iefttseÃÃ into thp patient. tf operated at the same ratP then there i.s stÃbstanfiiaily no net infiÃsion into the patient. A small amount of residual blood mixed with the saline is taken to the waste bag (4), 8. This process results in a washing of the system with saline.
9. Additional system cleaning is possible through an agftation mode. In this mode the fluid is moved forvuard and back such thatttÃrbuiertce in the flow occurs. During this process both pumps can be tased.
10. As a final step, the tubing between the junction and the patient, inelÃÃding the extension set (11), can be further cteaned by th.e irzCtssion of saline by both the flush pump atid the blood puÃnp. The use of both pumps in combination increases the overall for flow tttraugh this tubing area and helps to create turbulent fiow that aids in cteanÃng 1E1. Between blood samplings, the system can be placed in a keep vein open mode (K'JO). In this mode a small amount of saline oan be i.nfused to keep the blood access po-nt open.
[00881 Characteristics of tlfiodified Push Pull Example Embodirherit. The example embodiment of Figure 20 has similar characteristics as those of the exxampie embodiment depicted in Figure 5, and has the additiot3ai advantage of using a smaller overall blood withdrawal amount.
The example embodiment of Figure 20 can also rapidly clean the tubing section between the junction a~id the patient, and operate iwith reduced overal:l pressures. Additionally, the circuit can be operated in a manner where the hematocrit of the patient's blood is used to optimize oircuit performance by modifying the pump oontroi.
The use of hematocrit as a control variable ean further redtÃo~e the ar-nount of blood voittÃdrawrt and the maximum pressures required.
The use of the flush line in a bidirectional mode has several distinct advantages. Ouring the fttiat washing the rate of flow to the extension set at reasonable pressures can be greater than those oWaÃrÃed by tising only the blood pump. 1n addition to improved washing, the flush line oati be tiserf to "parit" a diluted leading segment. Specifically, the initial draw can be performed by the fftish pcirnp (3) scioh that the blood saline junction is moved into the right side of the circuit. After the blood/saline jtÃnctfon has passed and an undiluted sample has progressed to the T-junetion, the left side of the oircuit can be activated via the blood pump and a blood segment with a better defined saline/blood tÃoanctary transported to the measurement sensor.. As ietÃer fittings tae#ween the extension set and the standard catheter are a major source of blood/saline mixing the ability to "park" this mixed segment can be advantageous.

[00891 Central ~I~;naus.Qperatiort:, The ability to '"parkY the blood segment can be especially 'srnportant 3yhen using the systetn on a centraà venous catheter (CVC). All rgcares in this disclosure show the use of the system on peripheral venous catheters; which typicaÃÃy have volumes of less than 500 lalM .
In the case of a cesttral venous catheter, the volumes in the catheter can become quite tatge, around I
ml, since that they can extend for tip to 3 feet in the patient. This increased vaiumr-, and #ength of tij>/zing increases the amount of dead volume that must be withdrawn and increases the mixing at with the biood/saÃirte 6aoyndary. Given the 1argervolumes preceding the undiluted blood segment, it can be desirable to "park" the blood from the GVG near the access location instead of transporting it through 7 feet of tubing to the measurement sensor. Ãn operation, it has been found advantageons to use larger diameter tubing in the right side afthe circuit atid smaller diamet>;:r tubing in the left side. The use of larger diameter tubing ertabtes a more rapid draw from the CVC line, while smaller tciblng used to connect the glucose sensor has been found to rninimize the total volume of biood.
removed from the patient.
[00901 Push Pull System witti Two Peristaltic Pumps and Modified Sensor t..+acation.
Figure 23 is a schematir, illustration of an example blood access system implemented based upon a pull-push meohanism. The example circuit is simÃÃarto that depicted in Fig re 20 tytit the glucose sensor is in a different location. The system comprises a catheter (or similar blood access device) (12) in fluid r.tirnmonication with the vascular system of a patient, A tubing extension (11) (if required) extends from the catheter (12) to a junction (13). A first side ofthejunctÃon (13) connects with fluid transport apparatus (8) such as tubing (for reierence purposes called the left side" of the blood loop); a second side of the junction (13) connects with fluid transport apparatus (9) such as tubing (for reference purposes called the "right side" of the blood loop). An air detector (15) that can serve as a: leak detector, a pressure measurement device (17), and a glucose sensor (2) maunt vn the right side of the bload loop. A tubing reservoir 16 mounts with the right side cf the blood loop, and is in fluid comrnutlication with ablooef pump (S), which is in fluid communicatian with a receptacle or channel for waste, depicted in the figure as a bag {4}. A blaod pump (1) mounts with the left side (8) of the systern:, arid is in fluid communication with a reservoir (18) of ftuid such as saline. A blood detector (19) serves as a leak detector mounts on the teft side of the blood IoQp.An extension tubing set (11) can (and in rnai}y applicatio-ls, will be required to) moui3t between the blood access device (12) and the junctÃort (13). .Ari extension set is generaily a small length oftobing used to between a standard catheter and the blood access d.Ã-oi'rrit. This extension set adds additional dead voturne to the system, and adds other jonctions that, can be complicate cÃeaning.
Elements of the system and their operation are further described.. below.
j4t191J Blood satnple and tneasctrement pracess - SubsectEient Siocsd Sat-nplin~. In operafÃon the circuit shown in Figiire 23 operates in a manner very similar to the "paricu method descrihed above. A blood sample can be drawn into the right side (g) and transported to the glucose meas rernetit site, or a portion of the blood can be drawn and parked into the left side (8) first (as discLtssed more fully above). The following example operational sequence can be stiitable; othersectuences can also be tased. For an initial sample, the tubing between the pafient and the pcimp (1) can be filled with saline as a start cor#dition.
5ubseqcerct measurements can be achieved wittt operatiort as #'alÃows:
Ã.. Pump (1) initiates the blood draw by drawing blood upthrc-ugh jurartion{i 3).

2.. The withdrawal continues as blood passes throafgh the junction (13) }Ãr3Ãii an undiluted segmertt. of blood #s present at the juiicficat3 (13) 3. . Pump (1) stops and pu3np {3} di'aw.s the undiluted segment toward the gfucvse sensor (2).
4, r-oilrÃwir<g removal of an appreprÃate blood segment, pump (1) eail be activatect in a mai7iier that cleans the tubing frctn the: jzÃncticn (13) to the patient and ccnctÃrrentiy helps to push the undiluted segment to the glucose sensor (2).
5. Fcitc;vir g completion of ttEe gtucose rnesssarernent, pump (3) can be activated such that majority of blood is re infusert intiD the patient.
6. At the paitit the majority of blood has been retumeci to the patient, pump (1) can be activated and the direction of pump (3) reversed such that the circuit is effeetivety ciearied. The small amount of residual blood mixed with the sa#ine Is takeÃi to the waste bag {4}, 7, Between blood sampiings, the system can be placed in a keep vein Qparr mode (KVO). In this mcade a small amorÃr3t of saline can be int'tÃsei to keep the blood accF;Ss point open.
100$2j Acfvanta-ges of pressure measLirement. The systems as shown throughout this disclosure can use two pressure measurement devices which may or may not be specifically identified in each figure. These devices can be utilized to irteÃÃtiÃy accfusians in the circÃÃit during withdrawai and infusion as well as -the location of the occlusion. Additionally, the pressure sensors can be usedta effectively estimate the hernatrÃcrit of the blood. The pressure transducer on the flush line eÃfectively measures pressures close to the patient, while the pressure measurement device oti the blood ecce.ss line rneasures the pressure at the btrÃrÃd ptarrzp. The pressure gradient is a ftÃncficn of volume and tsema#ocr#t.
The volume pumped is known, and thus the pressure gradient can be used 1cs estimate the hematcerit of the blood being withdrawn.
(0093] Figure 20 shows the ose of two peristaltic pumps. In use peristaltic pumps create a pressure wave when the tubing is no tocager compressed by the roller mechanism. Ttte r-haracteristics of this pressure wave when transrrtitted through blood or saline are defined. Men the air or an air Wtabie is preseF3f in the systern the overall compliance of the system is ctramaticatiy aitereci and the characteristics ofttÃis pressure wave are altered. By usiÃig one Or both of'the pressure measurement devices as a pressure wave chsrrac.ter#zaticti system, the device can detect the presence of aire~nhali in the circ.Ãit:
[00941 The particular sizes and equ.ipment discussed above are cited merety to illustrate particular embodiments of the iEivsntian. It is contemplated that the use of the invention cas3 involve wrrtpanerÃts having clitferent sizes and characteristics. It is intended that the scope of the inventton be defined by the claims appended hereto.

Claims (129)

Claims What is claimed is:

1. An apparatus for measuring an analyte in blood taken from a patient, comprising;
a. An analyte measurement system;
b. A fluidics system, adapted to remove blood from a body, transport a portion of the removed blood to the analyte measurement system for measurement, infuse a portion of the blood measured by the analyte measurement system back into the patient, flow a maintenance substance to the analyte measurement system without infusing a substantial amount of the maintenance substance into the patient, and flow at least a portion of the maintenance substance from the analyte measurement system to a waste channel.

2. An apparatus as in Claim 1, wherein the maintenance substance is a fluid that cleans the analyte measurement system.

3. An apparatus as in Claim 1, wherein the maintenance substance is a fluid that provides a calibration measurement using the analyte measurement system.

4. An apparatus as in Claim 1, wherein the analyte is glucose, and the analyte measurement device is a glucose measurement device.

5. An apparatus as in Claim 4, wherein the glucose measurement device comprises one or more of:
electrochemical sensor, microfluidic sensor, micropost sensor, fluorescent measurement device, and an enzyme-based sensor, a spectroscopic measurement sensor,

6. An apparatus for determining an analyte property in blood, comprising:
a. a blood removal element, adapted to communicate blood with the circulatory system of a patient;
b. a fluid junction having three ports in fluid communication with each other, the first port in fluid communication with the blood removal element;
c. a source of maintenance fluid;
d. a channel for waste;
e. an analyte sensor having first and second fluid ports;
f. a first fluid control system, in fluid communication with and adapted to control fluid flow between the second port of the junction, the first port of the analyte sensor, and the source of maintenance fluid;
a second fluid control system, in fluid communication with and adapted to control fluid flow between the third port of the junction, the second port of the analyte sensor, and the waste channel.

7. An apparatus as in Claim 6, wherein the first fluid control system comprises:
a. a first pump, connected between the second port of the junction and the first port of the analyte sensor;

b. a first flow control element, connected between the first port of the analyte sensor and the source of maintenance fluid.

8. An apparatus as in Claim 6, wherein the first fluid control system comprises:
a. a first flow control element, connected between the second port of the junction and the first port of the analyte sensor;
b. a first pump, connected between the first port of the analyte sensor and the source of maintenance fluid.

9. An apparatus as in Claim 6, wherein the first fluid control system comprises:
a. a first pump, connected between the third port of the junction and the second port of the analyte sensor;
b. a first flow control element, connected between the second port of the analyte sensor and the waste channel.

10. An apparatus as in Claim 6, wherein the first fluid control system comprises:
a. a first flow control element, connected between the third port of the junction and the second port of the analyte sensor;
b. a first pump, connected between the second port of the analyte sensor and the waste channel.

11. An apparatus as in Claim 8, wherein the second fluid control system comprises:
a. a second flow control element, connected between the third port of the junction and the second port of the analyte sensor;
b. a second pump, connected between the second port of the analyte sensor and the waste channel.

12. An apparatus as in Claim 8, wherein the second fluid control system comprises:
a. a second pump, connected between the third port of the junction and the second port of the analyte sensor;
b. a second flow control element, connected between the second port of the analyte sensor and the waste channel.

13. An apparatus as in Claim 7, wherein the second fluid control system comprises:
a. a second flow control element, connected between the third port of the junction and the second port of the analyte sensor;
b. a second pump, connected between the second port of the analyte sensor and the waste channel,

14. An apparatus as in Claim 6, wherein the analyte sensor is a glucose sensor.

15. An apparatus as in Claim 6, wherein the waste channel comprises a bag adapted to receive and store waste fluid.

16. An apparatus as in Claim 6, wherein the maintenance fluid source comprises a bag containing satine solution.

17. A method of determining an analyte property of blood using an apparatus as in Claim 6, comprising:
a. operating the first fluid control system and the second fluid control system to transport blood from the blood removal element to either the first or second fluid control system;
b. operating the first fluid control system and the second fluid control system to transport at least a portion of the blood transported in step a to the analyte sensor;
c. determining the analyte property using the analyte sensor.

18. A method as in Claim 17, further comprising d) operating the first fluid control system and the second fluid control system to transport at least a portion of the blood in the analyte sensor to the blood removal element.

19. A method as in Claim 17, further comprising d) operating the first fluid control system and the second fluid control system to transport maintenance fluid from the source of maintenance fluid through the analyte sensor to the waste channel, without transporting a substantial volume of maintenance fluid to the circulatory system of the patient.

20. A method as in Claim 19, wherein the first fluid control system and the second fluid control system are operated such that variable fluid flow is attained during step d.

21. A method as in Claim 19, wherein the first fluid control system and the second fluid control system are operated such that fluid flows through the analyte sensor in opposite directions during two distinct times in step d.

22. A method as in Claim 17, wherein step b comprises operating the first fluid control system and the second fluid control system such that there is substantially no fluid flow through the blood removal element during step b.

23. An apparatus as in Claim 6, wherein the maintenance fluid produces a predetermined response from the analyte sensor.

24. A method as in Claim 17, wherein the maintenance fluid comprises a fluid that produces a predetermined response from the analyte sensor, and further comprising determining the response of the analyte sensor to maintenance fluid, and correcting determinations of analyte properties of blood to correct for analyte sensor performance indicated by a comparison of the actual analyte sensor response to the maintenance fluid with the predetermined response of the analyte sensor.

25. A method as in Claim 17, wherein the apparatus further comprises a pressure sensor responsive to fluid pressure in the apparatus, and wherein the method further comprises adjusting the fluid pump operation to prevent fluid pressure in the apparatus from exceeding a predetermined pressure.

26. A method as in Claim 17, further comprising, at a time when not operating according to steps a) through b), operating the first and second fluid control systems to push a maintenance fluid into the blood removal element at a rate sufficient to encourage the access to the patient's circulatory system to remain open.

27. A method as in Claim 17, wherein the apparatus further comprises a sensor operatively connected to at least a portion of the fluid paths between or within the elements of the apparatus, and wherein the operation of the first and second fluid control systems is controlled responsive to the pressure sensor to prevent occlusions from damaging the performance of the system.

28. A method as in Claim 17, wherein the apparatus further comprises a pressure sensor operatively connected to at least a portion of the fluid paths between or within the elements of the apparatus, and wherein the presence of air in a portion of the apparatus is determined from the pump operation and the pressure sensor.

29. An apparatus as in Claim 6, further comprising an air embolus detector operatively connected with at least one of the fluid paths in the apparatus.

30. An apparatus as in Claim 6, further comprising a pressure sensor operatively connected with at least one of the fluid paths in the apparatus.

31. An apparatus as in Claim 6, further comprising a blood leak detector operatively connected with at least one of the fluid paths in the apparatus.

32. An apparatus for measuring an analyte in blood, comprising:
a. A blood removal element, adapted to communicate blood with the circulatory system of a patient;
b. A first fluid transport apparatus, in fluid communication with the blood removal element;
c. A second fluid transport apparatus, in fluid communication with the blood removal element and the first fluid transport apparatus;
d. An analyte sensor, in fluid communication with the first fluid transport apparatus;
e. A fluid management system, in fluid communication with the first and second fluid transport apparatuses and adapted to control fluid flow in the first and second fluid transport apparatuses.

33. An apparatus as in Claim 32, wherein the fluid management system comprises:
a, a first pump, connected between the first fluid transport apparatus and the second fluid transport apparatus;
b. a fluid network, in fluid communication with at least one of the first fluid transport apparatus or the second fluid transport apparatus;
c. a second pump in fluid communication with the fluid network;
d. a waste channel in fluid communication with the fluid network;
e. a maintenance fluid reservoir in fluid communication with the fluid network.

34. An apparatus as in Claim 32, further comprising a pressure sensor operatively connected with at least one of the first fluid transport apparatus or the second fluid transport apparatus.

$5. An apparatus as in Claim 32, wherein the fluid management system comprises:
a. a first pump;
b. a second pump connected between the first fluid transport apparatus and the first pump;

c. wherein the first pump is in fluid communication with the first fluid transport, apparatus or second fluid transport apparatus;
d. a fluid reservoir in fluid communication with at least one of () the first fluid transport apparatus, (ii) the second fluid transport apparatus, and (iii) a path between the first and second pumps.

36. An apparatus as in Claim 32, wherein the fluid management system comprises a first pump connected with the first and second fluid transport apparatuses and a fluid reservoir, in fluid communication with either the first or second fluid transport apparatus such that the pump can cause fluid to flow in the first and second fluid transport apparatuses independently.

37. A method of determining an analyte property of blood using an apparatus as in Claim 35, comprising:
a. Drawing fluid from the first fluid transport apparatus such that blood flows from the blood removal element into the first fluid transport apparatus and to the analyte sensor;
b. Determining the analyte property of the blood using the analyte sensor;
c, Transporting blood from the first fluid transport apparatus to the second fluid transport apparatus;
d. infusing blood from the second fluid transport apparatus to the blood removal element.

38. A method of determining an analyte property of blood as in Claim 37, further comprising:
a, Using a sensor to indicate the arrival of blood at a predetermined location in the first fluid transport apparatus;
b. Determining the volume of the combination of the blood removal element and the first fluid transport apparatus from the circulatory system of the patient to the sensor from the operating parameters of the first and second pump and the sensor indication of the arrival of blood, and using the determined volume in subsequent control of the pumps.

39. An apparatus for measuring an analyte in blood, comprising:
a, a blood removal element, adapted to communicate blood with the circulatory system of a patient;
b. a first fluid transport apparatus, in fluid communication with the blood removal element;
c, a second fluid transport apparatus, in fluid communication with the blood removal element and the first fluid transport apparatus;
d. an analyte sensor, in bidirectional fluid communication with at least one of the first fluid transport apparatus and second fluid transport apparatus;
e. a first fluid pump, mounted with the first fluid transport apparatus such that the first fluid pump can draw fluid into and push fluid out of the first fluid transport apparatus;
f. a second fluid pump, in fluid communication with the second fluid transport apparatus;
g. a maintenance fluid reservoir, in fluid communication with the first fluid pump and adapted to supply a maintenance fluid to the first fluid pump;
h. a waste system, in fluid communication with the second fluid pump.

40. An apparatus as in Claim 39, further comprising an air embolus detector operatively connected with at least one of the first fluid transport apparatus and the second fluid transport apparatus.

41. An apparatus as in Claim 39, further comprising a pressure sensor operatively connected with at least one of the first fluid transport apparatus and the second fluid transport apparatus.

42. An apparatus as in Claim 39, further comprising a fluid reservoir in fluid communication with the sensor and with the pump.

43. An apparatus as in Claim 39, further comprising a blood leak detector operatively connected with at least one of the first fluid transport apparatus and the second fluid transport apparatus.

44. A method of determining an analyte property of blood using an apparatus as in Claim 39 where the analyte sensor is in fluid communication with the first fluid transport apparatus,, comprising:
a. Operating the first fluid pump to draw blood from the blood removal element into the first fluid transport apparatus and to the analyte sensor;
b. Determining the analyte property of the blood using the analyte sensor;
c, operating the first pump to draw maintenance fluid from the maintenance fluid reservoir and push a sufficient volume of maintenance fluid into the first fluid transport apparatus that an operative volume of the blood in the first fluid transport apparatus is infused into the patient using the blood removal element;
d. Operating the first pump to draw maintenance fluid from the maintenance fluid reservoir and push maintenance fluid into the first fluid transport apparatus, and operating the second pump to draw fluid from the first fluid transport apparatus and through the second fluid transport apparatus to the waste system, where the flow rates of the first and second pumps are such that an insubstantial volume of maintenance fluid is infused into the patient through the blood removal element.

45. A method as in Claim 44, wherein step b) is performed at least in part while blood is flowing through the analyte sensor.

46. A method as in Claim 44, wherein in step d) the first and second pumps are operated such that variable flow is attained in the first fluid transport apparatus, the second fluid transport apparatus, or both.

47. An apparatus as in Claim 39, further comprising a fluid network, and a flow control device between the sensor and the fluid network, and wherein the pump is in fluid communication through a flow control device with the fluid network, and wherein the maintenance fluid reservoir is in fluid communication through a flow control device with the fluid network.

48. An apparatus as in Claim 39, wherein the second pump is in fluid communication with the second fluid transport apparatus through a flow control device, and in fluid communication with the waste system; and further comprising a passive reservoir in fluid communication with the pump in the first fluid transport apparatus; and further comprising a fluid communication path from the fluid reservoir to the second pump.

49. A method as in Claim 44, further comprising, during step a), operating the second pump to prevent fluid pressure in the first fluid transport apparatus from exceeding a predetermined pressure.

50. A method as in Claim 44, further comprising, during step a), operating the first pump to prevent fluid pressure in the second fluid transport apparatus from exceeding a predetermined pressure,

51. A method of determining an analyte property of blood using an apparatus as in Claim 47, comprising:
a. Operating the first fluid pump to draw a sufficient volume of blood from the blood removal element into the first fluid transport apparatus;
b. Operating the first fluid pump to transport the blood in the first fluid transport apparatus to the analyte sensor while operating the second fluid pump to supply maintenance fluid from the maintenance fluid reservoir through the second fluid transport apparatus to the first fluid transport apparatus;
c. Determining the analyte property of the blood using the analyte sensor;
d. Operating the first and second fluid pumps such that an operative volume of the blood withdrawn in step a) is infused into the patient using the blood removal element;
e. Operating the first and second fluid pumps to push maintenance fluid through the first and second fluid transport apparatuses, where the flow rates of the first and second pumps are such that an insubstantial volume of maintenance fluid is infused into the patient through the blood removal element.

52. An apparatus as in Claim 35, further comprising:
a. a waste channel in fluid communication with at least one of (i) the first fluid transport apparatus, (ii) the second fluid transport apparatus, and (iii) a path between the first and second pumps, b. a maintenance fluid reservoir in fluid communication with at least one of (i) the first fluid transport apparatus, (ii) the second fluid transport apparatus, and (ii) a path between the first and second pumps.

53. An apparatus as in Claim 32, wherein the fluid management system comprises:
a. a first pump connected between the first fluid transport apparatus and the second fluid transport apparatus;
b. a second pump in fluid communication with the first fluid transport apparatus or the second fluid transport apparatus;
c. a fluid reservoir in fluid communication with at least one of (i) the first fluid transport.
apparatus, (ii) the second fluid transport apparatus, and (iii) the second pump.

5C A method of determining an analyte property of blood using an apparatus as in Claim 53, comprising:
a. Drawing fluid from the first fluid transport apparatus such that blood flows from the blood removal element into the first fluid transport apparatus and to the analyte sensor;
b. Determining the analyte property of the blood using the analyte sensor;

c. Transporting blood from the first fluid transport apparatus to the second fluid transport apparatus;
d. Infusing blood from the second fluid transport apparatus to the blood removal element.

55. A method of determining an analyte property of blood using an apparatus as in Claim 39 where the analyte sensor is in fluid communication with the second fluid transport apparatus, comprising:
a. Operating the second fluid pump to draw blood from the blood removal element into the second fluid transport apparatus and to the analyte sensor;
b. Determining the analyte property of the blood using the analyte sensor;
c. Operating the second pump to push an operative volume of the blood in the second fluid transport apparatus into the patient using the blood removal element;
d. Operating the first pump to draw maintenance fluid from the maintenance fluid reservoir and push maintenance fluid into the first fluid transport apparatus, and operating the second pump to draw fluid from the first fluid transport apparatus and through the second fluid transport apparatus to the waste system, where the flow rates of the first and second pumps are such that an insubstantial volume of maintenance fluid is infused into the patient through the blood removal element.

56. A method as in Claim 44, wherein step b) is performed at least in part while blood is flowing through the analyte sensor.

57. A method as in Claim 44, wherein in step d) the first and second pumps are operated such that at some time during step d) flow is reversed through the first fluid transport apparatus, the second fluid transport apparatus, or both.

58. A method as in Claim 51,wherein, during step b), less than a substantial volume of blood is withdrawn from the patient.

59. A method as in Claim 2551 wherein, during step c), at least some maintenance fluid is infused into the patient.

60. An method for measuring an analyte in blood taken from a patient comprising:
a. removing a sample of blood from the patient;
b. transporting the sample of blood in a sterile manner to an analyte measurement system;
c, measuring the analyte parameter in the transported sample using the analyte measurement system;
d. transporting at least a portion of the measured blood to the patient in a sterile manner and infusing the portion into the patient;
e. transporting a maintenance substance to the analyte measurement system without infusing a substantial amount of the maintenance substance into the patient;
f. transporting at least a portion of the maintenance substance from the analyte measurement system to a waste channel.

61. An apparatus for determining an analyte property of blood, comprising:

a. a blood removal element, adapted to communicate blood with the circulatory system of a patient;
b. A first fluid transport apparatus, in fluid communication with the blood removal element;
c. A second fluid transport apparatus, in fluid communication with the blood removal element and the first fluid transport apparatus;
d. A fluid pump, mounted with the first fluid transport apparatus such that the pump can draw fluid into and push fluid out of the first fluid transport apparatus;
e. A fluid reservoir, in fluid communication with the fluid pump and adapted to supply a maintenance fluid to the fluid pump;
f. An analyte sensor, in fluid communication with the second fluid transport apparatus:
g. A waste system, in fluid communication with the second fluid transport apparatus.

62. An apparatus as in Claim 61, further comprising a return fluid transport apparatus, in fluid communication with the analyte sensor and with the circulatory system of the patient.

63. An apparatus as in Claim 61, wherein the fluid pump comprises a hydraulically actuated syringe.

64. An apparatus as in Claim 63, wherein;
a. the blood removal element comprises a catheter;
b. the first fluid transport apparatus comprises flexible tubing;
c. the fluid reservoir comprises a bag containing maintenance fluid;
d. the hydraulically actuated syringe comprises:
i. a syringe having a pumping port, with the pumping port connected to the first fluid transport apparatus, and with the pumping port connected via a flow control system to the catheter and to the second fluid transport apparatus, where the flow control system allows either, both, or neither of the catheter and the second fluid transport apparatus to be placed in fluid communication with the pumping port;
ii. a hydraulic drive system, having a source of drive pressure connected with a drive port of the syringe, where the syringe draws fluid into the syringe, drives fluid out of the syringe, or maintains a current fluid state, responsive to the drive pressure.

65. An apparatus as in Claim 61, wherein the blood removal element comprises a flow control device configurable to allow fluid to pass therethrough and configurable to substantially prevent fluid from passing therethrough.

66. A method of determining an analyte property of blood using an apparatus is in Claim 66, comprising;
a. Configuring the blood removal element to allow fluid to pass, and operating the fluid pump to draw an operative volume of blood from the blood removal element into the first fluid transport apparatus;
b. Configuring the blood removal element to substantially prevent fluid from passing, and operating the fluid pump to draw maintenance fluid from the fluid reservoir and push blood from the first fluid transport apparatus into the second fluid transport apparatus and to the analyte sensor;
c. Determining the analyte property using the analyte sensor, d. Operating the fluid pump to push maintenance fluid through the first and second fluid transport apparatuses and flush blood from the analyte sensor.

87. A method as in Claim 66, wherein step b) comprises:
a. Configuring the blood removal element to substantially prevent fluid from passing, and operating the fluid pump to draw maintenance fluid from the fluid reservoir and push an operative volume of blood from the first fluid transport apparatus into the second fluid transport apparatus;
b. Configuring the blood removal apparatus to allow fluid to pass, and operating the fluid pump to draw maintenance fluid from the fluid reservoir and push blood in the first fluid transport apparatus, if any, and a sufficient volume of maintenance fluid from the first fluid transport apparatus into the blood removal element to clean the blood removal element;
c. Configuring the blood removal element to substantially prevent fluid from passing, and operating the fluid pump to draw maintenance fluid from the fluid reservoir and push maintenance fluid from the first fluid transport apparatus into the second fluid transport apparatus, pushing blood in the second fluid transport apparatus to the analyte sensor.

68. A method as in Claim 66, wherein the analyte property determination in step c) is performed at least partly while blood is flowing in the analyte sensor.

69. A method as in Claim 66, wherein the pump is operated in step d) with such that variable flow is produced in at least one of the first fluid transport apparatus, the second fluid transport apparatus, and the analyte sensor.

70. An apparatus as in Claim 61, wherein the maintenance fluid comprises a saline solution.

71. An apparatus as in Claim 61, wherein the maintenance fluid produces a known response from the analyte sensor.

72. A method as in Claim 66, wherein the maintenance fluid comprises a fluid that produces a known response from the analyte sensor, and further comprising determining the response of the analyte sensor to maintenance fluid, and correcting determinations of analyte properties of blood to correct for analyte sensor performance indicated by a comparison of the analyte sensor response to the maintenance fluid with the known response of the analyte sensor.

33. A method as in Claim 66, wherein the apparatus further comprises a pressure sensor responsive to fluid pressure in the apparatus, and wherein the method further comprises adjusting the fluid pump operation to prevent fluid pressure in the apparatus from exceeding a predetermined pressure.

74. A method as in Claim 66, further comprising, at a time when not operating according to steps a) or b), configuring the flow control device to allow fluid to pass, and operating the fluid pump to push maintenance fluid into the blood removal element at a rate sufficient to encourage the access to the patient's circulatory system to remain open.

75. A method as in Claim 66, wherein the apparatus further comprises a pressure sensor operatively connected to at least one of the first and second fluid transport apparatuses, and wherein the fluid pump operation is controlled responsive to the pressure sensor to prevent occlusions from damaging the performance of the system.

76. A method as in Claim 66, wherein the apparatus further comprises a pressure sensor operatively connected to at least one of the first and second fluid transport apparatuses, and wherein the presence of air in any of the blood removal element, the first fluid transport apparatus, or the second fluid transport apparatus, is determined from the pump operation and the pressure sensor.

77. A method as in Claim 76, wherein the presence of air is determined from the dynamic compliance of the fluid in any of the blood removal element, the first fluid transport apparatus, or the second fluid transport apparatus.

78. An apparatus for determining an analyte property in blood, comprising:
a. a blood removal element, adapted to communicate blood with the circulatory system of a patient;
b. an analyte measurement system, adapted to determine a desired property of blood;
c. a sample, drive system in fluid communication with the blood removal element and with the analyte measurement system, adapted to receive a blood sample from the blood removal element and transport if to the analyte measurement system.

79. An apparatus as in Claim 78, wherein the sample drive system is adapted to receive a blood sample comprising a first volume of blood, and transport at least a portion of the blood sample to the analyte measurement system without requiring substantially more than the first volume of blood to be supplied by the blood removal element.

80. An apparatus as in Claim 78, wherein the sample drive system is adapted to supply maintenance fluid to the blood removal element.

81. An apparatus as in Claim 78, wherein the sample drive system is in fluid communication with the analyte measurement system via a fluid transport apparatus, and wherein the sample drive system is adapted to move blood into the fluid transport apparatus and then to move a drive material into the fluid transport apparatus such that the drive material pushes the blood to the analyte measurement system.

82. An apparatus as in Claim 81, wherein the drive material comprises a maintenance fluid.

83. An apparatus as in Claim 82, wherein the maintenance fluid produces a known response from the analyte measurement system.

84. An apparatus as in Claim 82, wherein the maintenance substance is a fluid that cleans the analyte measurement system.

85. An apparatus as in Claim 82, wherein the maintenance substance is a fluid that provides a calibration measurement using the analyte measurement system.

86. An apparatus as in Claim 78, wherein the analyte is glucose, and the analyte measurement device is a glucose measurement device.

87. An apparatus as in Claim 81, wherein the drive material comprises polyethylene glycol,

88. An apparatus as in Claim 81,wherein the drive material comprises an inert gas or air.

89. An apparatus as in Claim 78, wherein the sample drive system is in fluid communication with the analyte measurement system via a fluid transport apparatus, and wherein the sample drive system is adapted to move a plug material into the fluid transport apparatus, then move blood into the fluid transport apparatus and then to move a drive material into the fluid transport apparatus such that the drive material pushes the plug material and the blood to the analyte measurement system.

90. An apparatus as in Claim 78, wherein the analyte measurement system comprises one or more of:
electrochemical sensor, microfluidic sensor, micropost sensor, fluorescent measurement device, an enzyme-based sensor, a spectroscopic measurement sensor.

91. A method of determining an analyte property of blood using an apparatus as in Claim 78, comprising:
a. Controlling the sample drive system to draw a blood sample from the blood removal element;
b. Controlling the sample drive system to transport a portion of the blood sample to the analyte measurement system;
c. Determining the analyte property using the analyte measurement system.

92. A method as in Claim 91, wherein the apparatus further comprises a waste channel in fluid communication with the analyte measurement system, and wherein the method further comprises controlling the sample drive system to transport blood from the analyte measurement system to the waste channel.

93. A method as in Claim 91, further comprising controlling the sample drive system to move at least a portion of the blood sample to the patient.

94. A method as in Claim 91 further comprising controlling the sample drive system to push a maintenance fluid into blood removal element.

95. A method as in Claim 94, wherein the maintenance fluid comprises a saline solution.

96. A method as in Claim 91, further comprising operating the sample drive system to prevent fluid pressure in the apparatus from exceeding a predetermined pressure.

97. A method as in Claim 91,further comprising, at a time when not operating according to step a), operating the sample drive system to transport maintenance fluid into the blood removal element at a rate sufficient to encourage the access to the patient's circulatory system to remain open.

98. A method as in Claim 91, wherein the apparatus further comprises a pressure sensor operatively connected to at least one fluid path within the apparatus, and wherein the sample drive system operation is controlled responsive to the pressure sensor to prevent occlusions from damaging the performance of the apparatus,

99. A method as in Claim 91,wherein the apparatus further comprises a pressure sensor operatively connected to at least one fluid path within the apparatus, and wherein the presence of air in one or more of the blood removal element, the sample drive system, or the analyte measurement system, is determined from the sample drive system operation and the pressure sensor.

100. A method as in Claim 99, wherein the presence of air is determined from the dynamic compliance of fluid in the apparatus.

101. A method of determining an analyte property of blood using an apparatus as in Claim 81, comprising;

d. Controlling the sample drive system to draw a blood sample tom the blood removal element;
e. Controlling the sample drive system to transport a portion of the blood sample into the fluid transport apparatus;
f. Controlling the sample drive system to transport drive material into the fluid transport apparatus and displace the blood therein such that the blood therein reaches the analyte measurement system;
g. Determining the analyte property using the analyte measurement system.

102. A method as in Claim 101, wherein the drive material comprises a material that produces a predetermined response from the analyte measurement system, and wherein the method further comprises operating the sample drive system to transport drive material into the fluid transport apparatus such that drive material reaches the analyte measurement system, and determining the actual response of the analyte measurement system to the drive material therein, and using a comparison of the actual response to the predetermined response to calibrate measurements of blood with the analyte measurement system.

103. A method of determining an analyte property of blood using an apparatus as in Claim 89, comprising h. Controlling the sample drive system to draw a blood sample from the blood removal element;
i. Controlling the sample drive system to move a plug material into the fluid transport apparatus;
then j. Controlling the sample drive system to transport a portion of the blood sample into the fluid transport apparatus;

k. Controlling the sample drive system to transport drive material into the fluid transport apparatus and displace the blood therein such that the plug material and then the blood therein reaches the analyte measurement system;
l. Determining the a-analyte property using the analyte measurement system.

104. An apparatus as in Claim 78, wherein the sample drive system comprises:
m. A first fluid transport apparatus (A2), in fluid communication with the blood removal element;
n. A second fluid transport apparatus (B), in fluid communication with the first fluid transport apparatus and with the blood removal element;
o. A sample system (38), in fluid communication with the first fluid transport apparatus and adapted to draw blood from the blood removal element into the first fluid transport apparatus, and adapted to move blood from the first fluid transport apparatus (A2) into the second fluid transport apparatus (B);

p. A third fluid transport apparatus (C);
q. A flow control element (32), mounted so as to receive fluid from the second fluid transport apparatus (B) and deliver fluid to the third fluid transport apparatus (C);
r. A waste channel (46), in fluid communication with the analyte measurement system (49);
s. A drive system (39), in fluid communication with the third fluid transport apparatus (C), and adapted to move fluid in the third fluid transport apparatus (C) away from the flow control element (32) and to the analyte measurement system (49) and waste channel (45).

145. An apparatus as in Claim 104, wherein the drive system is further adapted to introduce a plug material into the third fluid transport apparatus.

106. An apparatus as in Claim 106, wherein the plug material comprises polyethylene glycol.

107. An apparatus as in Claim 105, wherein the plug material comprises an inert gas or air.

108. An apparatus as in Claim 104, wherein the sample system comprises (j) a source of maintenance fluid and (k) a pump connected between the first fluid transport apparatus and a source of maintenance fluid.

109. An apparatus as in Claim 104, wherein the sample system comprises (j) a source of maintenance fluid, (k) a waste channel, (l) a pump in fluid communication with the first fluid transport apparatus, and in fluid communication with the source of maintenance fluid such that the pump can transport maintenance fluid to the first fluid transport apparatus, and in fluid communication with the waste channel such that the pump can transport fluid from the first fluid transport apparatus to the waste channel.

110. An apparatus as in Claim 109, wherein the sample system further comprises an air detector mounted with the first fluid transport apparatus.

111. An apparatus as in Claim 109, wherein the sample system comprises a pressure sensor mounted with the first fluid transport apparatus.

112. An apparatus as in Claim 105, wherein the drive system comprises a pump connected between a source of plug material and the third fluid transport apparatus.

113. An apparatus as in Claim 104, wherein the drive system comprises (j) a source of plug material, (k) a source of drive fluid, and (l) a drive pump in fluid communication with the third fluid transport apparatus, and with the source of plug material such that the drive pump can transport plug material from the source of plug material to the third fluid transport apparatus, and in fluid communication with the source of drive fluid such that the drive pump can transport drive fluid from the source of drive fluid to the third fluid transport apparatus.

114. An apparatus as in Claim 113, wherein the drive fluid comprises air.

115. A method of determining an analyte property of blood using an apparatus as in Claim 104, comprising:
t. Controlling the sample system to draw blood from the circulatory system of a patient into the first fluid transport apparatus;

u. Controlling the sample system to move at least some of the blood in the first fluid transport apparatus into the second fluid transport apparatus;
v. Controlling the sample system to move at least some of the blood in the second fluid transport system into the third fluid transport apparatus;
w. Controlling the drive system to move at least some of the blood in the third fluid transport apparatus to the analyte measurement system;
x. Determining the analyte property of the blood using the analyte measurement system.

116. A method as in Claim 115, further comprising controlling the drive system to move blood from the third fluid transport apparatus to the waste channel.

117. A method as in Claim 115. further comprising controlling the sample system to move blood from the first fluid transport apparatus to the patient.

118. A method as in Claim 115, further comprising controlling the sample system to push blood from the first fluid transport apparatus to the patient, and controlling the sample system to push maintenance fluid into the first fluid transport apparatus.

119. A method of determining an analyte property of blood using an apparatus as in Claim 105, comprising:
y. Controlling the sample system to draw blood from the circulatory system of a patient into the first fluid transport apparatus;
z. Controlling the sample system to move blood from the first fluid transport apparatus into the second fluid transport apparatus;
aa. Controlling, the drive system to move a plug of plug material into the third fluid transport apparatus;
bb. Controlling the sample system to move at least some of the blood in the second fluid transport system into the third fluid transport apparatus, pushing the plug material into the third fluid transport apparatus ahead of the blood;
cc. Controlling the drive system to move the blood and plug in the third fluid transport apparatus to the analyte measurement system;
dd. Determining the analyte property of the blood using the analyte measurement system.

120. A method as in Claim 119, further comprising controlling the drive system to move blood and the plug from the third fluid transport apparatus to the waste channel.

121. A method as in Claim 119, further comprising controlling the sample system to move blood from the first fluid transport apparatus to the patient.

122. A method as in Claim 119, further comprising controlling the sample system to push maintenance fluid into the first fluid transport apparatus.

123. A method as in Claim 119, further comprising controlling the drive system to move a second plug into the third fluid transport apparatus after the sample system has moved blood into the third fluid transport apparatus.

124. A method as in Claim 115, wherein the apparatus further comprises a source of maintenance fluid that produces a predetermined response from the analyte measurement system in fluid communication with the sample system, and wherein the method further comprises controlling the sample system to push maintenance fluid into the third fluid transport apparatus, and controlling the drive system to transport the maintenance fluid to the analyte measurement system, and determining the response of the analyte measurement system to the maintenance fluid, and correcting determinations of analyte properties of blood to correct for analyte measurement system performance indicated by a comparison of the analyte measurement system response to the maintenance fluid with the known response of the analyte measurement system.

125. A method as in Claim 115, further comprising operating the sample system to prevent fluid pressure in the first fluid transport apparatus from exceeding a predetermined pressure.

126. A method as in Claim 115, further comprising, at a time when not operating according to steps a) or b), operating the sample system to transport maintenance fluid into the blood removal element at a rate sufficient to encourage the access to the patient's circulatory system to remain open.

127. A method as in Claim 115, wherein the apparatus further comprises a pressure sensor operatively connected to at least one of the first and second fluid transport apparatuses, and wherein the sample system operation is controlled responsive to the pressure sensor to prevent occlusions from damaging the performance of the system.

128. A method as in Claim 115, wherein the apparatus further comprises a pressure sensor operatively connected to at least one of the first and second fluid transport apparatuses, and wherein the presence of air in one or more of the blood removal element, the first fluid transport apparatus, or the second fluid transport apparatus, is determined from the pump operation and the pressure sensor.

129. A method as in Claim 125, wherein the presence of air is determined from the dynamic compliance of the fluid in the apparatus.