Patent Application
20120065482
This invention relates to the field of the measurement of blood analytes, and more specifically to the measurement of analytes such as glucose in blood that has been temporarily removed from a body.
More than 20 peer-reviewed publications have demonstrated that tight control of blood glucose significantly improves critical care patient outcomes. Tight glycemic control (TGC) has been shown to reduce surgical site infections by 60% in cardiothoracic surgery patients and reduce overall ICU mortality by 40% with significant reductions in ICU morbidity and length of stay. See, e.g., Furnary, Tony, Oral presentation at 2005 ADA annual, session titled “Management of the Hospitalized Hyperglycemic Patient;” Van den Berghe et al., NEJM 2001; 345:1359. Historically, caregivers have treated hyperglycemia (high blood glucose) only when glucose levels exceeded 220 mg/dl. Based upon recent clinical findings, however, experts now recommend IV insulin administration to control blood glucose to within the normoglycemic range (80-110 mg/dl). Adherence to such strict glucose control regimens requires near-continuous monitoring of blood glucose and frequent adjustment of insulin infusion to achieve normoglycemia while avoiding risk of hypoglycemia (low blood glucose). In response to the demonstrated clinical benefit, approximately 50% of US hospitals have adopted some form of tight glycemic control with an additional 23% expected to adopt protocols within the next 12 months. Furthermore, 36% of hospitals already using glycemic management protocols in their ICUs plan to expand the practice to other units and 40% of hospitals that have near-term plans to adopt TGC protocols in the ICU also plan to do so in other areas of the hospital.
Given the compelling evidence for improved clinical outcomes associated with tight glycemic control, hospitals are under pressure to implement TGC as the standard of practice for critical care and cardiac surgery patients. Clinicians and caregivers have developed TGC protocols that use IV insulin administration to maintain normal patient glucose levels. To be safe and effective, these protocols require frequent blood glucose monitoring. Currently, these protocols involve periodic removal of blood samples by nursing staff and testing on handheld meters or blood gas analyzers. Although hospitals are responding to the identified clinical need, adoption has been difficult with current technology due to two principal reasons.
Fear of hypoglycemia. The target glucose range of 80-110 mg/dl brings the patient near clinical hypoglycemia (blood glucose less than 50 mg/dl). Patients exposed to hypoglycemia for greater than 30 minutes have significant risk of neurological damage. IV insulin administration with only intermittent glucose monitoring (typically hourly 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., lain Mackenzie et al., “Tight glycaemic control: a survey of intensive care practice in large English Hospitals;” Intensive Care Med (2005) 31:1136. In addition, handheld meters require procedural steps that are often cited as a source of measurement error, further exacerbating the fear (and risk) of accidentally taking the blood glucose level too low. See, e.g., Bedside Glucose Testing systems, CAP today, April 2005, page 44.
Burdensome procedure. Most glycemic control protocols require frequent glucose monitoring and insulin adjustment at 30 minute to 2 hour intervals (typically hourly) to achieve normoglycemia. Caregivers recognize that glucose control would be improved with continuous or near-continuous monitoring. Unfortunately, existing glucose monitoring technology is incompatible with the need to obtain frequent measurements. Using current technology, each measurement requires removal of a blood sample, performance of the blood glucose test, evaluation of the result, determination of the correct therapeutic action, and finally adjustment to the insulin infusion rate. High measurement frequency requirements coupled with a labor-intensive and time-consuming test places significant strain on limited ICU nursing resources that already struggle to meet patient care needs.
Limitations of Finger-Stick Technology To implement TGC protocols using today's manual, finger-stick technologies requires many steps, is technique sensitive and has opportunities for user errors. Using these technologies require removal of a blood sample, placement of just the right amount of blood on a test strip, evaluation of the result, determination of the correct glucose or insulin dose using a complex algorithm, and finally adjustment to the insulin infusion rate. In a recent study published in the America College of Surgeons in 2006, Taylor et al. noted that while implementing a TGC protocol, errors were found in the implementation of the protocol in 47% of all patients. Half of the errors were considered major, such as missing two or more glucose measurements in a row and insulin dosing errors. See Taylor et al., Journal of American College of Surgeons, 202, 1 (2006), which is incorporated herein by reference. The current manual method of TGC requires multiple types of equipment and at least two hours of nursing time per patient per day to implement. Even with all of this equipment and time spent, the targeted glycemic range of 80-110 mg/dl is difficult to achieve and maintaining patients in this range is even more difficult.
Medication errors are a significant and growing problem that can result in tragic loss of life and significant cost increases to the health-care community. Recent studies have listed medical errors as the eighth leading cause of death, ahead of motor vehicle accidents, breast cancer or AIDS. The American Hospital Association estimates that medical errors account for between 44,000 and 98,000 U.S. deaths each year. From a financial perspective, research indicates that nationally, the annual cost of preventable adverse drug events in the U.S. is about $6 billion. Over 770,000 patients are injured because of medication errors every year. Medication errors occur in nearly 1 of every 5 doses given to patients in the typical hospital. Reported rates of adverse drug events (ADEs) range from 2.4 to 6.1 ADEs per 100 admissions or discharges, or 9.1 to 19 ADEs per 1000 patient days.
Medication errors often arise from errors in drug administration, which account for 38% of medication errors. Only 2% of drug administration errors are intercepted. Safety at the point of care is one of the greatest areas for potential improvement in the medication use process. 54% of potential ADEs are associated with IV medications. Studies have found that ADEs occur between 2.9 and 3.7 percent of hospitalizations. 61% of the serious and life-threatening errors are associated with IV medications. Insulin has been described as the most dangerous IV medicine, with special protocols and checks recommended to help prevent life-threatening errors. See “Reducing Variability in High Risk Intravenous Medication Use”, Center for Medication Safety and Clinical Improvement, 2005, Cardinal Health, which is incorporated herein by reference.
The first concepts of an artificial pancreas were conceived in the 1970's. Such systems offer the promise of complete automation—the patient's blood glucose would be completely and perfectly controlled with no human user intervention. See “Report of the Automated Control of Insulin Levels Committee”, Committee Report (DRA 5), Institute for Alternative Futures, p. 9, September, 2006, which is incorporated herein by reference. However, any error in the measurement, infusion determination, or infusion system can lead to catastrophic medication errors, and so such systems have seen little use.
Accordingly, there is a need for a semi-automated medication management system that reduces the chance of missed measurements, infusion calculation errors, or infusion control errors while still involving a human clinician in the final infusion decision.
Development of Continuous Glucose Monitors. There has been significant effort devoted to the development of in-vivo glucose sensors that continuously and automatically monitor an individual's glucose level. Such a device would enable individuals to more easily monitor their glucose light levels. Most of the efforts associated with continuous glucose monitoring have been focused on subcutaneous glucose measurements. In these systems, the measurement device is implanted in the tissue of the individual. The device then reads out a glucose concentration based upon the glucose concentration of the fluid in contact with the measurement device. Most of the systems implant the needle in the subcutaneous space and the fluid measured under measurement is interstitial fluid.
As used herein, a “contact glucose sensor” is any measurement device that makes physical contact with the fluid containing the glucose under measurement. Standard glucose meters are an example of a contact glucose sensor. In use a drop of blood is placed on a disposable strip for the determination of glucose. An example of a glucose sensor is an electrochemical sensor. An electrochemical sensor is a device configured to detect the presence and/or measure the level of analyte in a sample via electrochemical oxidation and reduction reactions on the sensor. These reactions are transduced to a electrical signal that can be correlated to an amount, concentration, or level of analyte in the sample. Another example of a glucose sensor is a microfluidic chip or micro post technology. These chips are a small device with micro-sized posts arranged in varying numbers on a rectangle array of specialized material which can measure chemical concentrations. The tips of the microposts can be coated with a biologically active layer capable of measuring concentrations of specific lipids, proteins, antibodies, toxins and sugars. Microposts have been made of Foturan, a photo defined glass. Another example of a glucose sensor is a fluorescent measurement technology. The system for measurement is composed of a fluorescence sensing device consisting of a light source, a detector, a fluorophore (fluorescence dye), a quencher and an optical polymer matrix. When excited by light of appropriate wavelength, the fluorophore emits light (fluoresces). The intensity of the light or extent of quenching is dependent on the concentration of the compounds in the media. Another example of a glucose sensor is an enzyme based monitoring system that includes a sensor assembly, and an outer membrane surrounding the sensor. Generally, enzyme based glucose monitoring systems use glucose oxidase to convert glucose and oxygen to a measurable end product. The amount of end product produced is proportional to the glucose concentration. Ion specific of electrodes are another example of a contact glucose sensor.
As used herein, a “glucose sensor” is a noncontact glucose sensor, a contact glucose sensor, or any other instrument or technique that can determine the glucose presence or concentration of a sample. As used herein, a “noncontact glucose sensor” is any measurement method that does not require physical contact with the fluid containing the glucose under measurement. Example noncontact glucose sensors include sensors based upon spectroscopy. Spectroscopy is a study of the composition or properties of matter by investigating light, sound, or particles that are emitted, absorbed or scattered by the matter under investigation. Spectroscopy can also be defined as the study of the interaction between light and matter. There are three main types of spectroscopy: absorption spectroscopy, emission spectroscopy, and scattering spectroscopy. Absorbance spectroscopy uses the range of the electromagnetic spectrum in which a substance absorbs. After calibration, the amount of absorption can be related to the concentration of various compounds through the Beer-Lambert law. Emission spectroscopy uses the range of the electromagnetic spectrum in which a substance radiates, The substance first absorbs energy and then I radiates this energy as light. This energy can be from a variety of sources including collision and chemical reactions. Scattering spectroscopy measure certain physical characteristics or properties by measuring the amount of light that a substance scatters at certain wavelengths, incidence angles and polarization angles. One of the most useful applications of light scattering spectroscopy is Raman spectroscopy but polarization spectroscopy has also been used for analyte measurements. There are many types of spectroscopy and the list below describes several types but should not be considered a definitive list. Atomic Absorption Spectroscopy is where energy absorbed by the sample is used to assess its characteristics. Sometimes absorbed energy causes light to be released from the sample, which may be measured by a technique such as fluorescence spectroscopy. Attenuated Total Reflectance Spectroscopy is used to sample liquids where the sample is penetrated by an energy beam one or more times and the reflected energy is analyzed. Attenuated total reflectance spectroscopy and the related technique called frustrated multiple internal reflection spectroscopy are used to analyze liquids. Electron Paramagnetic Spectroscopy is a microwave technique based on splitting electronic energy fields in a magnetic field. It is used to determine structures of samples containing unpaired electrons. Electron Spectroscopy includes several types of electron spectroscopy, all associated with measuring changes in electronic energy levels. Gamma-ray Spectroscopy uses Gamma radiation as the energy source in this type of spectroscopy, which includes activation analysis and Mossbauer spectroscopy. Infrared Spectroscopy uses the infrared absorption spectrum of a substance, sometimes called its molecular fingerprint. Although frequently used to identify materials, infrared spectroscopy also is used to quantify the number of absorbing molecules. Types of spectroscopy include the use of mid-infrared light, near-infrared light and uv/visible light. Fluorescence spectroscopy uses photons to excite a sample which will then emit lower energy photons. This type of spectroscopy has become popular in biochemical and medical applications. It can be used with confocal microscopy, fluorescence resonance energy transfer, and fluorescence lifetime imaging. Laser Spectroscopy can be used with many spectroscopic techniques to include absorption spectroscopy, fluorescence spectroscopy, Raman spectroscopy, and surface-enhanced Raman spectroscopy. Laser spectroscopy provides information about the interaction of coherent light with matter. Laser spectroscopy generally has high resolution and sensitivity. Mass Spectrometry uses a mass spectrometer source to produce ions. Information about a sample can be obtained by analyzing the dispersion of ions when they interact with the sample, generally using the mass-to-charge ratio. Multiplex or Frequency-Modulated Spectroscopy is a type of spectroscopy where each optical wavelength that is recorded is encoded with a frequency containing the original wavelength information. A wavelength analyzer can then reconstruct the original spectrum. Hadamard spectroscopy is another type of multiplex spectroscopy. Raman spectroscopy uses Raman scattering of light by molecules to provide information on a sample's chemical composition and molecular structure. X-ray Spectroscopy is a technique involving excitation of inner electrons of atoms, which may be seen as x-ray absorption. An x-ray fluorescence emission spectrum can be produced when an electron falls from a higher energy state into the vacancy created by the absorbed energy. Nuclear magnetic resonance spectroscopy analyzes certain atomic nuclei to determine different local environments of hydrogen, carbon and other atoms in a molecule of an organic compound. Grating or dispersive spectroscopy typically records individual groups of wavelengths. As can be seen by the number of methods, there are multiple methods and means for measuring glucose in a non-contact mode.
Note that the glucose sensors are referred to via a variety of nomenclature and terms throughout the medical literature. As examples, glucose sensors are referred to in the literature as ISF microdialysis sampling and online measurements, continuous alternate site measurements, ISF fluid measurements, tissue glucose measurements, ISF tissue glucose measurements, body fluid measurements, skin measurement, skin glucose measurements, subcutaneous glucose measurements, extracorporeal glucose sensors, in-vivo glucose sensors, and ex-vivo glucose sensors. Examples of such systems include those described in U.S. Pat. No. 6,990,366 Analyte Monitoring Device and Method of Use; U.S. Pat. No. 6,259,937 Implantable Substrate Sensor; U.S. Pat. No. 6,201,980 Implantable Medical Sensor System; U.S. Pat. No. 6,477,395 Implantable in Design Based Monitoring System Having Improved Longevity Due to in Proved Exterior Surfaces; U.S. Pat. No. 6,653,141 Polyhydroxyl-Substituted organic Molecule Sensing Method and Device; US patent application 20050095602 Microfluidic Integrated Microarrays For Biological Detection; each of the preceding incorporated by reference herein.
In the typical use of the above glucose sensors require calibration before and during use. The calibration process generally involves taking a conventional technology (e.g., fingerstick) measurement and correlating this measurement with the sensors current output or measurement. This type of calibration procedure helps to remove biases and other artifacts associated with the implantation of the sensor in the body. The process is done upon initiation of use and then again during the use of the device.
Testing of CGMS systems in the ICU setting. Since continuous glucose monitoring systems (CGMS) provide a continuous glucose measurement, it can be desirable to use these types of systems for implementation of tight glycemic control protocols. 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 continuous glucose monitors in the standard manner of placing them in the tissue such that they measure interstitial glucose. A second avenue of investigation has used the sensors in direct contact with blood via an extracorporeal blood loop. Summary information from existing publications is presented below.
“Experience with continuous glucose monitoring system a medical intensive care unit”, by Goldberg at al, Diabetes Technology and Therapeutics, Volume 6, Number 3, 2004.
“The use of two continuous glucose sensors during and after surgery” by Vriesendorp et al., Diabetes Technology and Therapeutics, Volume 7, Number 2, 2005. In a summary conclusion the authors' state that the technical performance and accuracy of continuous glucose sensors need improvement before continuous glucose can sensors can be used to implement strict glycemic control protocols during and after surgery.
“Closed loop glucose control in critically ill patients using continuous glucose monitoring system in real-time”, by Chee et al, IEEE transactions on information technology in biomass and, volume 7, Number one, March 2003. The authors provide a summary comment that improvement of real-time sensor accuracy is needed. In fact the actual accuracy of the results generated showed that 64.6% of the sensor readings would be clinically accurate (zone b) while 28.8% would lead to in no treatment (zone b), as illustrated in
Problems with Existing CGMS. The present invention can address various problems recognized in the use of CGMS. The performance of existing CGMS when placed in the tissue or an extracorporeal blood circuit is limited. The source of the performance limitation can be segmented into several discrete error sources. The first is associated with the actual performance of the sensor overtime, while the second error grouping is associated with the physiology assumptions needed for accurate measurements.
General performance limitations: in a simplistic sense electrochemical or enzyme based sensors use glucose oxidase to convert glucose and oxygen to gluconic acid and hydrogen peroxide. An electrochemical oxygen detector is then employed to measure the concentration of remaining oxygen after reaction of the glucose; thereby providing an inverse measure of the 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 order to prevent interference in measurements from the hydrogen peroxide. In operation the system of measuring glucose requires that glucose be the rate limiting reagent of the enzymatic reaction. When the glucose measurement system is used in conditions where the concentration of oxygen can be limited a condition of “oxygen deficiency” can occur in the area of the enzymatic portion of the system and results in an inaccurate determination of glucose concentration. Further, such an oxygen deficit contributed other performance related problems for the sensor assembly, including diminished sensor responsiveness and undesirable electrode sensitivity. Intermittent inaccuracies can occur when the amount of oxygen present at the enzymatic sensor varies and creates conditions where the amount of oxygen can be rate limiting. This is particularly problematic when seeking the use the sensor technology on patients with cardiopulmonary compromise. These patients are poorly perfused and may not have adequate oxygenation.
Performance over time: in many conditions an electrochemical sensor shows drift and reduced sensitivity over time. This alteration in performance is due to a multitude of issues which can include: coating of the sensor membrane by albumin and fibrin, reduction in enzyme efficiency, oxidation of the sensor and a variety of other issues that are not completely understood. As a result of these alterations in sensor performance the sensors must be recalibrated on a frequent basis. The calibration procedure typically requires the procurement of a blood measurement and a correlation of this measurement with the sensor performance. If a bias or difference is present the implanted sensor'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, external measurement technique and is quite cumbersome to implement.
Physiological assumptions: for the sensor to effectively represent blood glucose values a strong correlation between the glucose levels in blood and subcutaneous interstitial fluid must exist. If this relationship does not exist, a systematic error will be inherent in the sensor signal with potentially serious consequences. A number of publications have shown a close correlation between glucose levels in blood and subcutaneous interstitial fluid. However, most of these investigations were performed under steady-state conditions only, meaning slow changes in blood glucose (<1 mg/dl/min). This restriction on the rate of change is very relevant due to the compartmentalization that exists between the blood and interstitial fluid. Although there is free exchange of glucose between plasma and interstitial fluid, a change in blood glucose will not be immediately accompanied by an immediate change of the interstitial fluid glucose under dynamic conditions. There is a so-called physiological lag time. The physiological lag time is influenced by many parameters, including the overall perfusion of the tissue. In conditions where tissue perfusion is poor and the rate of glucose change is significant the physiological lag can become very significant. In these conditions the resulting difference between interstitial glucose and blood glucose 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 intensive care unit or operating room typically have some type of cardiovascular compromise the needed agreement between ISF glucose and whole blood is not present.
Additional understanding with respect to the calibration of continuous glucose monitors can be obtained from the following references. U.S. Pat. No. 7,029,444, Real-Time Self Adjusting Calibration 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 monitor data. The method enables calibrating the calibration characteristics using the reference glucose values and the corresponding glucose monitor data. US patent application 2005/0143636 System and Method for Sensor Recalibration. The patent application described a methodology for sensor recalibration utilizing an array of data which includes historical as well as recent data, such as, blood glucose readings and sensor electrode readings. The state in the application, the accuracy of the sensing system is generally limited by the drift characteristics of the sensing element over time and the amount of environmental noise introduced into the output of the sensing element. To accommodate the inherent drift in the sensing element in the noise inherent in the system environment the sensing system is periodically calibrated or recalibrated.
Additional understanding with respect to sensor drift can be obtained from the following references. Article by Gough et al. in Two-Dimensional Enzyme Electrode Sensor for Glucose, Vol. 57, Analytical Chemistry pp 2351 et seq (1985). U.S. Pat. No. 6,477,395 Implantable Enzyme-based Monitoring System Having Improved Longevity Due to Improved Exterior Surfaces. The patent describes an implantable enzyme based monitoring system having an outer membrane that resists blood coagulation and protein binding. In the background of the invention, columns 1 and 2 the authors describe in detail the limitations and problems associated with enzyme-based glucose monitoring systems.
The operation of many of the embodiments disclosed herein involves the use of a maintenance fluid. 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, maintenance fluids can include fluids specifically used for calibrating the device or for cleaning the system, for other diagnostic purposes, and/or can include fluids that perform a combination of such functions.
Glucose sensors, both contact and noncontact, have different capabilities with respect to making accurate measurements in moving blood. For example, most strip based measurement technologies require an enzymatic reaction with blood and therefore have an operation incompatible with flowing blood. Other sensors can operate in a mode of establishing a constant output in the presence of flowing blood. Noncontact optical or spectroscopic sensors are especially applicable to conditions where the blood is flowing by the fact that they do not require an enzymatic reaction. For the blood access system described herein, one objective is to develop a system that does not result in blood clotting. Generally speaking blood that is stagnant is more prone to clotting than blood that is moving. Therefore the use of measurement systems that do not require stationery blood is beneficial. This benefit is especially relevant if the blood is to be re-infused into the patient.
In an instrument that operates in the intensive care unit on critically 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 after initial set-up and during operation. The system can function without any opening or closing or the system. Any operation that “opens” the system is a potential site of infection. Closed system transfer is defined as the movement of sterile products from one container to another in which the container's closure system and transfer devices remain intact throughout the entire transfer process, compromised only by the penetration of a sterile, pyrogen-free needle or cannula 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 due to the mechanical closures typically used.
In the development of a glucose measurement system for frequent measurements in the intensive care unit, the ability to operate in a sterile or closed manner is extremely important. In the care of critically ill patients the desire to avoid the development of systemic or localized infections is considered extremely important. Therefore, any system that can operate in a completely closed manner without access to the peripheral environment is desired. For example, blood glucose measurement systems that require the removal of blood from the patient for glucose determination result in greater infection risk due to the fact that the system is exposed to a potentially non-sterile environment for 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 risk, a noncontact spectroscopic glucose measurement is almost ideal as the measurement is made with light which is able to evaluate the sample without any increase in infection risk.
Sampling from a central venous catheter. The effective implementation of tight glycemic control protocols generally requires the frequent measurement of glucose. This measurement process typically requires the procurement of a blood sample that is representative of the patient's physiological status. Samples can be obtained from a variety of means, including without limitation peripheral IV's, arterial blood lines, midline catheters peripherally inserted central catheters, and central venous catheters. Central venous catheters can be a preferred means of access due to the frequency of use in the ICU and the ability to make blood withdrawals on a regular basis. Most central venous catheters are multi-lumen catheters with the number of lumens being selected based upon patient needs. Catheters are referred to as monoluminal, biluminal or triluminal, dependent on the actual number of tubes or lumens (1, 2 and 3 respectively). Some catheters have 4 or 5 lumens, depending on the reason for their use. The termination of the lumen in the body occurs at different locations. The termination point is typically referred to as a port. In the case of a multi-lumen catheter the port at the end of the catheter is defined as the distal port, with intervening ports referred to as medial ports and the port closest to the insertion into the body referred to as the proximal port. The catheter is usually held in place by a suture or staple and an occlusive dressing. Regular flushing with saline or a heparin-containing solution is performed to keep the line patent and prevent infection.
Central venous blood samples can be obtained through a variety of catheter types including a central venous catheter. Central venous catheters are utilized for many purposes to include drug infusion as well as blood sampling. When central venous catheters are utilized for procurement of a blood draw, nursing standards are very specific with respect to the procedure to be used. These standards require that all IV infusions be stopped and recommend a one minute wait time before drawing blood from the catheter. The rationale for both the stoppage and waiting period is to allow IV fluids and medications to be carried away from the catheter location such that the blood sample is not contaminated by the fluids being infused (the “infusate”). The mixing of IV fluids or medications in the blood sample is generally referred to as cross-contamination. Cross-contamination is the general process by which fluids being infused into the patient become present in the blood sample and can contaminate resulting measurements.
Although central venous catheters can be placed in a variety of locations, the typical placement is to have the tip 3-4 cm above the entrance to the right atrium. This places the tip in the center of the superior vena cava and the proximal opening about 6 cm back from the tip. The proximal port will typically be in the vein where the device was introduced; i.e. the brachial cephalic or internal jugular vein. The flow characteristics surrounding the ports of the central venous catheter can have direct influence on the possibility of cross-contamination. The superior vena cava is the main vein for the drainage of the superior aspect of the body. It is about 7 cm in length and is formed by the confluence of the brachiocephalic veins. It has no valves and ends in the right atrium. It is approximately 20 mm in diameter. The inferior vena cava has similar flow characteristics but the flow rates are strongly dependent upon exercise involving the lower extremity. Flow in the central vena cava is variable and is affected by the cardiac cycle and respiration.
Difficulties in tight glycemic control when using a central venous catheter. For blood glucose measurement systems that utilize a central venous access catheter for procurement of a blood sample for subsequent analysis or place a catheter in the superior or inferior vena cava, the potential impact of cross-contamination involving a glucose containing fluid can be quite dramatic. For example, if the patient is being infused with a 5% dextrose solution (5000 mg/dl), and 1% cross-contamination occurs, the measured glucose value can be in error by 50 mg/dl. Given that the typical target range for tight glycemic control is between 80 and 120 mg/dl, a potential over-estimation by 50 mg/dl can have serious consequences. As an example, the patient might be given additional insulin due to the inaccurately high glucose measurement result. The actual overall systemic glucose would be consequently decreased while the measured glucose might remain high due to the presence of glucose via cross-contamination. Cross-contamination with non-glucose containing fluids also can affect the measurement, but are typically less significant since they generally result in a decreased glucose measurement. The impact is simply volumetric so at a glucose value of 100 mg/dl a 10% dilution can result in a glucose measurement of 90 mg/dl, and such slightly low glucose readings are less likely to have such dramatic undesirable treatment errors.
Accordingly, there is a need for methods and apparatuses that allow accurate glucose measurements from catheters, especially central venous catheters, in the presence of infusion of substances including glucose.
Arterial Catheter method Since 2001, a number of intensive care units have adopted tight glycemic control protocols for the maintenance of glucose at close to physiological levels. The process of maintaining tight glycemic control requires frequent blood glucose measurements. The blood utilized for these measurements is typically obtained by procurement of a sample from a fingerstick, arterial line, or central venous catheter. Fingerstick measurements are generally considered undesirable due to the pain associated with the fingerstick process and the nuisance associated with procurement of a quality sample. Sample procurement from central venous catheters can also present problems since current clinical protocols recommend the stoppage of all fluid infusions prior to the procurement of a sample. Consequently, the use of arterial catheters has become more common. Arterial catheters are typically placed for hemodynamic monitoring of the patient and provide real-time continuous blood pressure measurements. These catheters are maintained for a period of time and used for both hemodynamic monitoring and blood sample procurement. Arterial catheters are not typically used for drug or intravenous feedings so issues associated with cross-contamination are minimized.
The process of procuring an arterial blood sample for measurement typically involves the following steps. The slow saline infusion used to keep the artery open is stopped and some type of valve mechanism such as a stopcock is opened to allow fluid connectivity to the mechanism for blood draw. The process of opening the stopcock and concurrently closing off fluid connectivity to the pressure transducer will cause a stoppage of patient pressure monitoring as the transducer no longer has direct fluid access to the patient. The sample procurement process is initiated. The initial volume drawn through the stopcock is saline followed by a transition period of blood and saline and subsequently pure blood. Generally, at the point where there is no or very little saline in the blood sample at the stopcock (or a knowable saline concentration), the measurement sample is obtained. The blood and saline sample obtained previously can be discarded or infused back into the patient.
In many intensive care units, a significant portion of blood samples obtained from arterial catheters are procured using blood sparing systems. In this process a leading sample containing both saline and blood is withdrawn from the patient and stored in a reservoir that lies beyond the sample acquisition port. A sample of blood that is free of saline contamination can then be procured at the sample port for measurement. Example embodiments of such blood sparing techniques include the Edward's VAMP system, shown in
Air bubbles represent a significant problem for hemodynamic monitoring systems as they change the overall performance of the system. Air bubbles can become trapped in the monitoring system during filling, blood sampling, or added later by manual flushing or continuous flush devices. The presence of an air bubble adds undesirable compliance to the system and tends to decrease the resonant frequency and increase the damping coefficient. The resonant frequency typically falls faster than the damping increases, resulting in a very undesirable condition.
In clinical use, a pressure monitoring system should be able to detect changes quickly. This is known as its “frequency response”. The addition of damping to a monitoring system will tend to decrease its responsiveness to changes in the frequency of the pressure waveform but prevents unwanted resonances. This is especially so if changes are occurring rapidly such as occur at high heart rates or with a hyperdynamic heart. During these conditions it is essential that the system have a high “natural” or “untamed” frequency response. The optimal pressure monitoring system should have a high frequency such that over damped or under damped waveforms are unlikely regardless of the degree of damping present. The relationship of frequency and camping coefficient have been explored and defined by Reed Gardner. This relationship is well described in “Direct Blood Pressure Measurements—Dynamic Response Requirements” anesthesiology pages 227-236, 1981, incorporated herein by reference.
Due to the existing performance requirements and the fact that air bubbles dramatically alter the performance of a typical hemodynamic monitoring system, it is clinical practice to have the clinician evaluate the system carefully for the presence of any air bubbles. As stated by Michael Cheatham in “Hemodynamic Monitoring: Dynamic Response Artifacts” (available from www.surgicalcriticalcare.net), perhaps the single most important step in optimizing dynamic response is ensuring that all transducers, tubing, stopcock, and injection ports are free of air bubbles. Air, by virtue of being more compressible than fluid, tends to act as a shock absorber within a pressure monitoring system leading to a over damped waveform with its attendant underestimation of systolic blood pressure and over estimation of diastolic blood pressure. The identification of air bubbles is typically done by visual inspection of the system as well as by a dynamic response test. In practice this dynamic response test is achieved by doing a fast-flush test. A fast flesh or square wave test is performed by opening the valve of the continuous flush device such that flow through the catheter tubing is actually increased to approximately 30 ml/hr versus the typical 1-3 ml/hr. This generates an acute rise in pressure within the system such that a square wave is generated on the bedside monitor. With closure of the valve, a sinusoidal pressure wave of a given frequency and progressively decreasing implicated is generated. A system with appropriate dynamic response characteristics will return to the baseline pressure waveform within one or two oscillations, as illustrated in
In almost any automated blood glucose monitoring system, the device must procure or withdraw a sample of blood from the body. This process may require a few milliliters of blood or only a few micro liters. Regardless of the amount, the process exposes the associated fluid column to pressure gradients, potentially different pressures and fluid flows. Therefore, the process of procuring a blood sample has the potential to create bubbles within the fluid column. The fluid column is not intended to be restrictive but to apply to any of the fluid associated with the automated sample measurement system. Solubility is the property of a solid, liquid or gas called solute to dissolve in a liquid solvent to form a homogeneous solution. The solubility of a substance strongly depends on the used solvent as well as on temperature and pressure. In the application of automated blood measurements, the liquid solvent is blood, saline or any intravenous solution. The solute is air, oxygen or any gas in the liquid solvent. Changers in solubility due to temperature or pressure may result in bubble formation. As a solution warms it will typically outgas due to a decrease in solubility with temperature. Changes in pressure can also result in bubbles. The solubility of gas in a liquid increases with increasing pressure. Henry's Law states that: the solubility of a gas in a liquid is directly proportional to the pressure of that gas above the surface of the solution. If the pressure is increased, the gas molecules are forced into the solution since this will best relieve the pressure that has been applied.
Bubbles may be formed due to cavitation. Cavitation is the formation of bubbles in a flowing liquid in a region where the pressure of the liquid falls below its vapor pressure. Cavitation can occur due to pumping at the low pressure or suction side of the pump. Cavitation can occur via multiple methods but the most common are vaporization, air ingestion (not always considered cavitation, but has similar symptoms), and flow turbulence
In a typical process of procuring a blood sample, a negative or reduced pressure is created so that the blood flows out of the body. This reduction in pressure creates an opportunity for bubble creation. Additionally, temperature differences between the human body, the ambient air, and any IV solutions also create the opportunity for bubble creation. Almost any form of pumping device creates some small degree of cavitation. Therefore, the process of attaching or combining a hemodynamic monitoring system with an automated blood measurement system creates the opportunity for bubble formation which in turn can result in poor performance of the hemodynamic monitoring system.
Hemodynamic pressure monitoring is unavailable during the procurement of the blood sample by either the syringe method or by use of a blood sparing system. If the standard stopcock is replaced with a 4-way stopcock it would allow the transducer and the blood sampling system to be in fluid connectivity with the patient. In such a situation the withdrawal process creates a pressure gradient that will limit the accuracy of the existing hemodynamic monitoring system.
The development of an automated blood glucose measurement system for use in the intensive care unit is highly desired due to reductions in labor, increased measurement frequency, and an improved ability to limit potentially dangerous conditions of hypoglycemia. The ability to attach such a system to an arterial access site is desired as catheter patency for blood sample procurement is typically better at an arterial access location than at a venous access site. As placement of an arterial catheter is considered a moderately invasive procedure, it is undesirable to require placement of two such catheters, one used for pressure monitoring and another for blood access. Thus, in clinical practice it is desirable to use one arterial access site for both hemodynamic monitoring as well as a blood access site for automated glucose measurement. Such sharing of a single site can result in hemodynamic monitoring disruption during the blood procurement process. For example, if the automated blood measurement system acquires a sample every 15 minutes, it will likely interfere with the hemodynamic pressure monitoring system so as to cause an alarm or produce inaccurate pressure measurements. The management of such an alarm typically requires nurse intervention, defeating some of the advantages sought with an automated blood measurement system. In addition to nuisance alarms, the real-time hemodynamic monitoring may be disrupted during the automated measurement process. In those patients that are hemodynamically unstable, such a disruption may be an unacceptable consequence of automated blood glucose monitoring.
Diabetes mellitus is an endocrine metabolic disorder resulting from a lack of insulin that affects over 170 million people worldwide. Improved glucose sensing would enable improved glycemic control, thereby delaying the onset of serious medical complications associated with diabetes. An indispensable tool for both diabetic and critically ill patients is a reliable blood glucose measurement method. Most diabetic patients currently use self-monitoring via finger pricking and test strips to check their blood glucose level and adjust their insulin dosage to maintain normal blood glucose concentrations. Although such self-monitoring of blood glucose has been an indispensable tool for diabetes therapy, it is fraught with difficulties. Frequent finger pricking is painful, costly, and inconvenient for the patient. As a result of this invasiveness, many diabetics frequently skip self-monitoring tests. Further, tight control of blood glucose is difficult to achieve without frequent glucose measurements. Intermittent measurements can be influenced by other changes in the patient's physical state and testing conditions. Glucose fluctuations during the day, and particularly during the night, are often missed using self-monitoring techniques.
One desirable system for the management of glycemia is a continuous in-vivo glucose monitoring method that could be coupled with an automated insulin pump for active closed-loop control of glucose level. In-vivo glucose sensing devices being developed comprise both implanted and noninvasive sensors. Invasive devices can be implanted intravascularly in the blood stream or interstitially under the skin, since the concentration of glucose within the interstitial fluid correlates with the glucose concentration in the blood. Alternate invasive technologies to measure blood glucose remove blood from the body for interrogation and analysis. This blood might be discarded or infused back into the body. Typically, if blood is infused, saline is also used which adds more fluid to the body. Noninvasive glucose sensors measure glucose concentrations in vivo without direct physical contact between the sensor and the biological fluid. Such noninvasive sensors are patient friendly and can eliminate biocompatibility problems. Most in-vivo glucose sensors are based on electrochemical or colorimetric/photometric detection techniques.
Colorimetric and photometric approaches can be used to monitor glucose levels directly. For example, vibrational spectroscopic approaches can use the unique vibration transitions within the glucose molecule. Vibrational spectroscopies include Raman spectroscopy and absorption spectroscopy in the mid- and near-infrared spectral regions. Raman spectroscopy can measure fundamental vibrational bands, but sensing applications have been hampered by the presence of a strong background fluorescence signal and low signal-to-noise ratio due to an inherently weak Raman signal. Glucose is a relatively simple monosaccharide molecule with strong and distinctive absorption features in the mid-infrared (MIR) region. Unfortunately, water and other non-glucose metabolites, such as proteins, amino acids, urea, fatty acids, and triglycerides also strongly absorb in the MIR.
Therefore, emphasis has shifted to the detection of molecular absorptions in the near-infrared (NIR) spectral region corresponding to combinations and overtones of fundamental glucose molecular vibrations. The strong OH and CH stretch bands in the 2900 to 3600 cm−1 MIR region can generate overtone and combination bands in the 700 to 1700 nm NIR region. Additional glucose-specific combinations of CH stretch and ring deformation bands occur at wavelengths greater than 2000 nm. Although the glucose absorptions in the NIR are unique, they are weaker and broader than the fundamental bands and also overlap with bands from other tissue components, such as water, fat, and hemoglobin. Therefore, multivariate chemical analysis methods can be used to extract glucose-specific spectral information.
Noninvasive optical sensors can use optical radiation to probe regions of tissue, such as the finger, tongue, or ear, and extract glucose concentration from a measured spectrum. Noninvasive NIR sensors use the “optical window” in the near infrared in which the absorbance by human biological tissue is lower compared to the visible or ultraviolet regions. However, these noninvasive NIR sensors can have measurement difficulties due to the weak glucose absorption peaks, relatively low glucose concentrations in human tissue, multiple interferences with non-glucose metabolites, variations in tissue hydration, blood flow, environmental temperature, and light scattering.
Fiber optic probes can be used for minimally invasive optical sensors. See Utzinger and Richards-Kortum, J. Biomedical Optics 8(1), 121 (2003), which is incorporated herein by reference. Fiber optic probes provide a flexible optical interface between a light source, spectrometric detector, and the tissue being interrogated so that the light source and detector can be located remote from the patient. A dual-fiber arrangement can be used for separate illumination and collection. The collection fiber optic can transport the remitted light from the interrogated tissue to the spectrometer.
An individual optical fiber typically comprises a core, a cladding, and a protective jacket. Fibers can be packed into bundles to provide a larger optical active area. Coupling optics can adapt the f-number of the light source to the numerical aperture of the fiber to optimize irradiance into the fiber. The ends of a fiber can be cleaved or polished for optimal coupling. Further, the exit surface can be beveled to deflect the light output or input. Probe geometries can comprise side-looking probes that use obliquely polished ends to deflect the output of the fiber in respect to the fiber axis, probes with diffuser tips to provide homogeneous illumination of large areas in canals and on surfaces, and refocusing probes that refocus the illumination or collection beam path to decrease or increase the sample volume illuminated.
Probe assemblies have also been used for indwelling light scattering spectroscopy for biomedical applications. See U.S. Pat. No. 6,366,726 to Wach et al., which is incorporated herein by reference. In particular, Raman spectroscopy can provide a means for chemical identification. With Raman spectroscopy, incident laser light is transmitted over an optical fiber to the sample medium and the Raman-scattered is returned via the same or another fiber to a spectrometer for analysis. The Raman-scattered light is color shifted from the incident illumination beam by a specific amount related to molecular band vibrations. Further, the intensity of the shifted return light correlates with the chemical concentration. However, in-vivo Raman spectroscopy using flat face, parallel illumination and collection fiber probes has been hampered by the inefficiency of scattered light collection. Wach describes several approaches to direct and manipulate illumination and receptivity zones to improve Raman-scattered light collection efficiency. These approaches include varying the numerical apertures of the illumination and collection fibers, use of confocal optics, bending the tips of the fibers to increase the overlapping region, shaping the fibers' end faces to create a refractive surface to manipulate the illumination and collection zones, and manipulating the light with light-shaping structures within the confines of the fiber assembly's internal structure. Therefore, the probe can be designed to have selective sensitivity to the Raman scattering signal by delivering light at one angle and collecting light at the appropriate angle to maximize the response. However, sensing applications based on Raman spectroscopy have been hampered by the silica-Raman effect and fiber fluorescence and the inherently low weak Raman signal.
Therefore, a need remains for an in-vivo continuous glucose monitoring method that uses an indwelling fiber optic probe to measure glucose concentration or presence in the near-infrared spectral region.
In-Vivo Glucose Sensors This invention relates to the measurement of blood analytes, and more specifically to the measurement of glucose in blood that has been temporarily removed from the body. Over the past 10 years there has been significant effort devoted to the development of in-vivo glucose sensors that continuously and automatically monitor an individual's glucose level. Such a device enables individuals to more easily monitor their glucose levels. Most of the efforts associated with continuous glucose monitoring have been focused on subcutaneous glucose measurements. In these systems, the measurement device is implanted into the tissue of the individual. The device then reads out a glucose concentration based upon the glucose concentration of the fluid in contact with the measurement device. Most of such systems implant a needle in the subcutaneous space and measure interstitial fluid.
As used herein, a contact glucose sensor is any measurement device that makes physical contact with a fluid containing the glucose to be measured. An example of a contact glucose sensor is an electrochemical sensor. A noncontact glucose sensor is any measurement method that does not require physical contact with the fluid containing the glucose under measurement. Example noncontact glucose sensors include sensors based upon spectroscopy, meaning sensors based on the interaction between light and matter. For the purposes of this application “glucose sensor” includes both contact sensors and noncontact sensors.
Almost all types of glucose sensors are subject to drift over time. Therefore the ability to periodically calibrate these sensors is often desired and necessary. Within the context of automated blood glucose measurements for use in the intensive care unit, a simple and easy to use calibration procedure is desired. Such a calibration procedure should not require nurse intervention and should maintain the overall sterility of the device. Calibration techniques that infuse excessive amounts of glucose into a patient can be undesirable (since maintenance of tight glycemic control is important in many medical settings, including OR and ICU settings).
In the case where the sensor drifts over time, a bias and slope correction can require subsequent validation. The use of bias and slope adjustments to improve calibration or prediction statistics for multivariate models is appropriate provided that the calibration is fully revalidated whenever bias and slope is adjusted. Bias and slope adjustments are another form of calibration transfer and use of bias and slope adjustments can be handled in the same fashion as any other calibration transfer. Prediction errors requiring continued bias and slope corrections indicate drift in reference method or changes in the character of the samples, sample handling, sample presentation, instrument response function, or wavelength stability. If a calibration model fails during the QC monitoring step, the performance of the instrument can be evaluated using the appropriate ASTM instrument performance test [E1944-98 (reapproved 2007), incorporated herein by reference], and any instrument problem that is identified can be corrected. If control samples are used, checks can be performed on the reference method to ensure that reference values are correct. If instrument maintenance is performed, calibration transfer or instrument standardization procedures, or both, can be followed to reestablish the calibration. The preceding information is cited from ASTM International E 1655-05, “Standard Practices for Infrared Multivariate Quantitative Analysis,” Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, Pa. 19428-2959, United States, 2007, incorporated herein by reference.
In general terms, the ability to calibrate a system and provide subsequent validation is a desired attribute of a blood analyte system. When evaluating an analyte sensor that has multiple analytes, a multitude of calibration samples can be needed to create confidence in the calibration and validation procedure.
In creating a blood access system for measurement of blood analytes, the process generally involves removing the blood from the patient to a measurement site. The measurement is then made by a variety of methods and the blood is either discarded or re-infused into the patient. Access to the patient is typically through a catheter including, as examples, peripheral venous lines, PIC lines, arterial lines and central venous lines. In many cases, the access line between the patient and the pumping system is typically filled with a fluid, such as saline. It is common practice to infuse a small amount of saline between blood draws or measurements to help maintain the patency of the access site. This is referred to herein as a “keep vein open” or “KVO” rate. At the initiation of a draw the fluid-filled line reverses flow and blood is pulled toward the measurement site. The junction between the blood and the fluid is referred to as the “blood-fluid junction”; mixing of the fluid with the blood near the junction creates a “transition zone”. As the blood is drawn from the patient through the tubing, the blood/fluid interface exhibits a parabolic flow profile and is characterized by a broadened transition zone of blood mixed with fluid. Additional dilution can occur due to tubing discontinuities. The transition zone between undiluted blood and fluid increases in extent as the draw continues. Since analyte measurement systems are often sensitive to dilution effects, measurement accuracy can be enhanced by providing a sample for measurement that has a known or controlled dilution, for example a constantly diluted sample, a minimally diluted sample, or an undiluted sample, can facilitate accurate measurements. Hereafter the reference to an “undiluted” sample simply refers not only to a blood sample that has not been diluted but also to any sample that is suitable for accurate determination of blood analytes due to a known or controlled dilution characteristic. Accordingly, an “undiluted” sample can have dilution but of a quality that can be controlled, sensed, or managed. To obtain a blood sample representative of the blood in the patient, the blood access system can pull the diluted blood in the transition zone beyond the measurement site. Thus, the total amount of blood drawn is greater than the volume of the tubing between the measurement site and the patient. This dilution issue is known in the medical community and is generally addressed by drawing a discard sample or by filling an extra reservoir with diluted blood. As an example, the Edward's VAMP system includes such a reservoir.
In some systems, it can be desirable to also follow the sample with fluid so as to minimize the amount of blood that is removed from the patient. In this case, a second transition zone is created behind the undiluted sample.
In a system with defined and predictable operating characteristics, the withdrawal volume needed for procurement of an undiluted sample can be established and fixed. In most real-world blood access systems too many variables change over time and the system must have the capability of determining the presence of an undiluted sample. Some of the variables that change over time and between patients include:
Length and/or volume of the access catheter: central venous catheters generally have more volume and a longer length than peripheral catheters;
Extension tubing: the clinical staff might add extension tubing to the blood access system;
Blood viscosity changes due to differences in blood composition;
Blood hematocrit differences that influence the pressure needed to move the fluid and mixing characteristics at the blood-saline junction;
Pump tubing differences, including differences in internal volume and or pumping efficiency;
Pump efficiency changes over time.
Due to these and other variables that can change over time, the system must be able to determine the presence of an undiluted sample and then initiate the analyte measurement process.
Peristaltic pumps are commonly used in medical applications because they enable bidirectional pumping and can also prevent flow when the pump motor is not moving. However peristaltic pumps can be prone to pump volume differences between tubing sets and within a tubing set over time. In a peristaltic pump the volume accuracy is dependent on the volume captured between two or more occluding points, the pump rollers. The captured volume between the rollers is then propagated through the pump creating flow. For the pump to be accurate this captured volume must be constant. When a peristaltic pump withdraws fluid from a line there is a vacuum generated in the inlet of the pump. This vacuum can cause the tubing to collapse, and the captured volume between the occluding rollers will be less than in non-collapsed tubing. This can be compensated to an extent by monitoring the pressure at the inlet of the pump, and by adjusting the pump speed to withdraw the correct total volume. However, over time the tubing can fatigue so that it collapses more easily and the capture volume drifts down. As a result, the accuracy of the pump decreases over time. When withdrawing fluid from a line, the amount of fatigue varies from tubing set to tubing set and the change in fatigue varies increasingly over time (see, e.g.,
The determination of volume can be made with a flow meter. A number of ultrasonic flow meters are available commercially. By knowing the flow rate and the time period the amount of volume pumped can be determined. Volume determination helps to compensate for pump efficiency changes but does not completely compensate for blood changes. Additionally, such flow meters are expensive relative to overall system cost objectives.
For a blood access system designed to measure blood anatytes, the system should be able to determine when the fluid withdrawn is suitable for measurement. Due to the possibility of changing parameters associated with the blood being withdrawn, the physical volume of the blood access system and the efficiency of the pump system, the use of a fixed draw volume or draw time is inadequate. It can be desirable to minimize the total amount of blood withdrawn due to fluid infusion needs, the desire to remove from the patient as little blood as possible, and the desire to expose the tubing set to a minimum amount of blood over time.
Proper determination of an analyte for a biological system requires procurement or acquisition of a sample that is representative of the biological system prior to analyte determination. For example, measurement of blood analyte values and other blood parameters (such as blood counts, coagulation parameters, and oxygenation status) in patients usually requires that a blood sample be drawn from the patient for analysis. Caregivers frequently draw blood samples for analysis from arterial or venous access lines that are also used to infuse fluids to the patient. This generally requires that a volume of blood and fluid be pre-drawn from the access line to clear the line of the infusion fluid between the sample port and the tip of the catheter in the patient's vessel so that the desired measurement is performed on sample of blood and not on infusion fluid that may be still in the line. After the pre-draw is complete, the pure blood sample is drawn for analysis. When the pre-draw is not performed or is of insufficient volume to completely clear the line of the non-blood fluid, the blood sample that is procured for analysis can contain an unknown amount of the infusion fluid. The result is a sample that provides an erroneous result, either due to simple dilution (in the case where the infusion fluid is simple saline) or due to a false change in the analyte or parameter of interest due to the contamination of the sample by the constituents of the infusion fluid. Errors of this type that are associated with sample procurement prior to analyte or parameter determination are known in the clinical community as pre-analytical errors, and are among the most common errors encountered in measurements of blood chemistry and other biological fluid samples. Such errors can result in the need to repeat tests, causing delays in making medical decisions or administering treatment. In some cases, such errors can lead to erroneous medical decisions, leading to serious and sometimes even fatal medical consequences for the patient.
In addition to dilution or contamination of a blood sample by infusion fluid due to insufficient volume of pre-sample, there are several other situations that can compromise the quality of the biological sample. Examples include:
Acquisition of a blood sample simultaneously with administration through an adjacent vascular access line of a therapeutic agent or fluid. This can cause acquisition of a non-representative sample if the blood sample were drawn before the fluid were evenly distributed and equilibrated throughout the systemic blood volume. Acquisition of a sample during administration of a fluid or agent can be contaminated with the co-infused substance.
Administration of large volume physiological therapy, such as blood transfusion or blood volume expanders. As before, a blood sample drawn during such therapy can be an unstable or nonrepresentative sample.
It can be desirable to determine the quality of the sample prior to making the determination of the analyte or parameter of interest of the biological sample, thereby preventing the reporting of analytical values that have pre-analytical error due to improper or inadequate sample procurement or acquisition.
Intensive Insulin Therapy Critically ill patients that require intensive care for more than five days have a 20% risk of death and substantial morbidity. Hyperglycemia associated with insulin resistance is common in critically ill patients, even those who do not suffer from diabetes. A recent paper published in November 2003 in the NEJM by Greet Van den Burghe et al hypothesized that hyperglycemia or relative insulin deficiency during critical illness may directly or indirectly confer a predisposition to complications such as severe infections, polyneuropathy, multiple-organ failure, and death. In nondiabetic patients with protracted critical illnesses, high serum levels of insulin-like growth factor-binding protein 1, which reflect an impaired response of hepatocytes to insulin, increase the risk of death. They performed a prospective, randomized, controlled trial at one center to determine whether normalization of blood glucose with intensive insulin therapy reduces mortality and morbidity among the critically ill patients.
Van Den Berghe et al were able to show dramatic improvements in patient's outcomes when patients had their blood glucose controlled tightly between 80 and 110 mg per deciliter during their ICU stay.
The trial performed was a prospective, randomized, controlled study involving adults admitted to the surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]).
At 12 months, with a total of 1,548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent. Also patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care.
Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter was shown to reduce morbidity and mortality among critically ill patients in the surgical intensive care unit. These results are even more exciting when overlaid with Oye et al. (Chest 99:685, 1991) findings that 8% of patients consumed 50% of cumulative ICU resources (measured by TISS points) (Therapeutic Intervention Scoring System). Garland et al. (AJRCCM 157:A302, 1998) had similar findings; 5% with the longest ICU lengths of stay consumed 20-48% of various ICU resources.
In the intensive treatment group, an insulin infusion was started if the blood glucose level exceeded 110 mg/dl, adjustment of insulin does was based upon whole-blood glucose measurements in arterial blood at 1 to 4 hour intervals with the use of a blood glucose analyzer. The dose of insulin was adjusted based upon a predetermined algorithm by a team if ICU nurses assisted by a study physician. These manual methods were extremely labor intensive and are not feasible for therapy adoption. In the conventional treatment group a continuous infusion of insulin was started if the blood glucose level exceeded 215 mg/dl and the infusion was adjusted to maintain a level between 180 and 200 mg/dl. On admission all patients were continuously with intravenous glucose (200 to 300 grams per 24 hrs). The next day total parenteral, combined parenteral and enteral feeding was instituted.
Diabetes companies are currently focused on implementing closed loop control for ambulatory diabetic patients where they have encountered a myriad of problems associated with blood glucose sensor accuracy and glucose level control due to the large fluctuations in patient metabolism and eating patterns, changes in sensor sensitivity due to the elapse of time and differences in patients, safety detection systems etc. Much research work is currently being focused to commercially produce an accurate long term implanted blood glucose sensor. It has been found that ensuring blood glucose sensor accuracy and having a fast responsive time are mutually exclusive for an implantable blood glucose sensor. Some glucose sensor manufacturers have focused on subcutaneous implanted sensors to avoid the pitfalls of sensor degradation due to fouling and clotting but these devices, while avoiding the need for blood contact, suffer from longer time constants and transport delays that make closed loop control very difficult. Non-invasive optical methods using near-infrared spectroscopy suffer from the affects of tissue variation and some manufacturers require the use of individual patient calibration making their use less desirable. Other sensors extract glucose through the skin by iontophoresis and measures the extracted sample electrochemically, using the glucose oxidase reaction. Direct contact with blood has been avoided due to clotting and fouling issues.
Thevenot in 1982 (Diabetes Care, Vol. 5 No. 3:184-189) recognized in his article that an implanted sensor would have to survive long-duration implantation in chemically harsh environment of the body. That the sensitivity would have 2 to 5% of the actual glucose level with a range of 10 to 200 mg/dl with little or no change due to long term drift or temperature dependence. Oberhardt in 1982 (Diabetes Care, Vol. 5 No. 3:213-217) recommended that the response of the sensor be 30 sec or less and that the sampling rate be 10 sec averaged over a 1 minute interval. No glucose has yet been proven to meet these requirements.
Many of the design constraints imposed by the ambulatory market are not valid for inpatient hospital ICU use and thus afford a new look at the design requirements. ICU patients are not ambulatory diabetic patients and are fed both parenterally and entrally. This avoids the large swings in levels of blood glucose seen in diabetic patients due to calorie intake at meal times and makes for a more even and predictable control system. Avoiding these large perturbations to the control system makes it easier to maintain glucose control. Implanted glucose sensors would be expected to work accurately for at least one year. This imposes a very large burden upon the sensor design which is currently one the biggest limitation in developing a viable implanted system. If the calibration of such a sensor were to fail it could have deleterious consequences for the patients. Schemes have been proposed to cross check the readings between the implanted sensor and standard finger stick sensors to overcome some of these limitations. Such a limitation does not exist if the sensor is only required for 3 to 5 days of use and independent periodic calibration can be instituted off line ensuring the accuracy of the sensor.
There is a significant need for an easy to use accurate glucose control therapy that can be instituted safely and effectively in the inpatient hospital setting in post surgical ICU patients. Such a therapy will reduce the incidence of mortality, sepsis and renal failure and can have dramatic costs savings for both hospitals and health care providers while improving patient quality of life and outcomes.
The present invention comprises methods and apparatuses that can provide measurement of glucose and other analytes with a variety of sensors without many of the performance-degrading problems of conventional approaches. An apparatus according to the present invention comprises a blood access system, adapted to remove blood from a body and infuse at least 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 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 removed blood back into the body. The use of a non-contact sensor with a closed system creates a system with minimal infection risk.
A method according to the present invention can comprise measuring the value of an analyte such as glucose at a first time; determining a second time from a patient condition, an environmental condition, or a combination thereof; then measuring the value of the analyte at the second time. The invention can be used with automated measurement systems, allowing the system to determine measurement times and automatically make measurements at the determined times, reducing operator interaction and operator error. The present invention also comprises methods and apparatuses for medication management based upon active authorization of medication infusion by a clinician that can provide for effective management of an analyte in a patient's blood, reducing the opportunities for human error common with current manual systems while still placing final control of the medication management with the human clinician.
The present invention comprises methods and apparatuses that can provide accurate measurement of glucose or other analytes from a multilumen catheter in the presence of infusion of substances, including glucose. Alternatively, the present invention provides an indwelling fiber optic probe that can be used to make blood glucose measurements through a central venous catheter. The probe can also be used to measure other metabolites, such as blood gases, lactate, hemoglobin and urea. The present invention comprises methods and apparatuses that can provide measurement of glucose and other analytes with a variety of sensors in connection with hemodynamic monitoring.
The invention relates to an automated calibration procedure for analyte sensors such as glucose sensors. The system can provide a calibration point at zero analyte concentration as well as a second calibration point at a known analyte concentration or other pre-determined points. The present invention enables a multitude of options in both calibration and validation to ensure effective operation of the system.
Example embodiments of the present invention provide methods and apparatuses that enable the detection of bubbles so that hemodynamic performance can be assured following an automated blood analyte measurement. An example apparatus according to the present invention comprises a blood access system, adapted to remove blood from a body and infuse at least a portion of the blood back into the body. The infusion of at least a portion of the blood back in to the body can be done in a manner to assure that no bubbles of clinical significance are injected into the patient. Additionally an example embodiment can assess for the presence of bubbles in the fluid column that can affect hemodynamic monitoring performance. If a condition exists where hemodynamic monitoring performance cannot be assured, an example embodiment can provide appropriate warning or corrective actions.
The present invention relates to a blood analyte measurement system for the procurement of blood samples for measurement of blood properties such as analyte concentration or analyte presence. A blood access system can be coupled with a measurement system such as an electrochemical sensor, and can also be used with other measurement modalities.
The use of an optical measurement in the blood access system enables the determination of a fluid sample appropriate for measurement on a real time basis. This information can be used to control the blood access system and related measurement processes. The optical measurement system can take a variety of forms, including light emitting diodes and detectors, spectrometers, and interferometers. Wavelength regions of relevance can span from the ultraviolet to the far infrared. The visible, near infrared and mid infrared spectral regions can be of particular interest.
The invention disclosed is not dependent upon the measurement method used and is applicable to indwelling electrochemical sensors, enzymatic sensors, sensors that work when in contact with blood, such as those made by Dexcom and Abbott, standard sensors that work on a sample of blood and other optical sensing methods that use serum, plasma, or ultra filtrate. Additionally, the method can work on any fluid-sample junction. Examples of such possible junctions include saline-serum, saline-plasma, and saline-ultra filtrate, and saline-supernatant from a centrifuged sample.
Advantages and novel features will become apparent to those skilled in the art upon examination of the following description or can be learned by practice of the invention. The advantages of the invention can be realized and attained by means of the methods, instrumentation architectures, and combinations specifically described in the disclosure and in the appended claims.
a,b,c) is a schematic illustration of the operation of an example embodiment of the present invention.
a illustrates the operation and fluid path of the extracorporeal blood circuit shown in
b illustrates the operation and fluid path of the extracorporeal blood circuit shown in
a to 104d are a series of diagrams shown in plan (104a and 104c) and in cross-section (104b and 104d) to depict the operation of a three port three-way stopcock.
a to 105c are a series of diagrams depicting the operation of the rotary solenoid.
The present invention comprises methods and apparatuses that can provide measurement of glucose and other analytes with a variety of sensors without many of the performance-degrading problems of conventional approaches. An apparatus according to the present invention comprises a blood access system, adapted to remove blood from a body and infuse at least 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 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 removed blood back into the body.
The performance of the analyte sensor in the present invention can be dramatically improved compared with conventional applications by minimizing various issues that contribute to degraded sensor performance over time and by providing for cleaning and calibrating the measurement sensor over time. The physiological lag problems associated with conventional tissue measurements can also be reduced with the present invention by making a direct measurement in blood or by ensuring that there is appropriate agreement between the ISF glucose level and that in whole blood.
Some embodiments of the present invention provide for effective cleaning of the sensor. If effectively cleaned at the end of each measurement, the amount of sensor fouling and/or drift can be minimized. Saline or another physiologically compatible solution can be used to clean the sensing element.
A typical glucose sensor used relies on a glucose-dependent reaction to measure the amount of glucose present. The reaction typically uses both oxygen and glucose as reactants. If either oxygen or glucose is not present, the reaction can not proceed; some embodiments of the present invention provide for total removal of one or the other to allow a zero point calibration condition. Saline or another physiological compatible solution that does not contain glucose could be used to effectively create a zero point calibration condition.
There can be limitations associated with a zero point calibration so that one may desire to use a calibration point with a glucose value above zero and preferably within the physiological range. Some embodiments of the present invention provide for such a calibration by exposing the sensor to a glucose containing solution with a known glucose concentration. This can effectively recalibrate the sensor and improve its accuracy. The ability to make frequent recalibrations enables a simplistic approach to maintaining overall sensor accuracy.
In many medical laboratory measurement products a two point calibration is used. Some embodiments of the present invention provide two types of calibrations to provide a two point calibration capability. A two point calibration can allow both bias and slope to be effectively determined and mitigated.
In practice the degree or amount of physiological lag observed between ISF glucose levels in whole blood glucose levels creates a significant error source. Some embodiments of the present invention reduce this source of error by placing the sensor in direct contact with blood.
Recognizing the several error sources, the present invention provides an accurate continuous or semicontinuous blood glucose measurement system for use in applications such as the intensive care unit. Some embodiments of the present invention place blood in contact with a sensing mechanism for a defined measurement period and then clean the sensor. Following cleaning of the sensor, a calibration point or points can be established. The present invention contemplates a variety of blood access circuits that can enable the sensor to be cleaned on a periodic basis and can allow for recalibration; illustrative examples are described below. In addition to providing a mechanism for improved sensor performance, the disclosed blood access systems can also provide methods for occlusion management, minimization of blood loss and minimization of saline used for circuit cleaning.
The example embodiments generally show a blood access system with the ability to control fluid flows at a location removed from the blood access console and near the patient. The ability to control fluid flows at this remote location does not necessitate the use of a mechanical valve or other similar apparatus that similarly directs or control flow at a point near the patient. Additionally it does not require nurse or other human intervention. For multiple reasons, including safety and reliability, it is desirable not to have a mechanical device, wires, or electrical power near the patient. As shown in many example embodiments, this capacity is enabled through the use of a pumping mechanism that provides for both fluid stoppage and movement. Additional capabilities are provided by bidirectional operation of the pumps, and by operation at variable speeds including complete stoppage of fluid flow. As used in the disclosure, operation may be the use of the pump as a flow control device to prevent flow. As shown in the example embodiments these capabilities can be provided through peristaltic pumps and syringe pumps. It is recognized by one of ordinary skill in the art that these capabilities can also be provided by other fluid handling devices, including as examples linear “finger” pumps, valveless rotating and reciprocating piston metering pumps, piston pumps, lifting pumps, diaphragm pumps, and centrifugal pumps. “Plunger” pumps to include syringe pumps as well as those that can clean a long thin flexible piece of tubing are considered. These types of plunger pumps have the advantage of removing or transporting the fluid without the need for a following fluid volume. For example, no follow volume is required when using a syringe pump.
The example embodiments generally show a sensor in contact with a blood access system. The sensor can be immersed or otherwise continuously exposed to fluid in the system. It can also comprise a noncontact sensor that interacts with fluid in the system. It can also comprise a sensor remote from the blood access system, where the sensor element in the example comprises a port or other sampling mechanism that allows a suitable sample of fluid from the system to be extracted and presented to the remote sensor. This type of sampling can be used with existing technology glucose meters and reagent strips.
Example Embodiment Comprising a Sensor and a Fluid Management System.
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, infused into the patient, or neither. The fluid management system (21) can also comprise a source of a suitable fluid such as saline, and manage fluid flow in the system such that saline is circulated through the left (2) and right (9) sides to flush or clean the system. The fluid management system can further comprise an outlet to a waste container or channel, and manage fluid flow such that used saline, blood/saline mix, or blood that is not desired to be returned to the patient (depending on the requirements of the application) is delivered to the waste container or channel.
Example Embodiment Comprising a Blood Loop System with a Syringe Pump.
Blood sample and measurement process. A first sample draw with the example embodiment of
1. Syringe pump (5) initiates a draw along the left side (2) of the blood loop.
2. The blood interacts with the sensor measurement cell (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. Sensor measurements can be made as the blood moves through the measurement cell (1).
4. As blood nears junction (13) the system can be stopped and the saline that was 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 via the withdrawal of syringe (5).
6. Withdrawal of blood by the syringe, either fully or partially, is stopped. Sensor sampling of the measurement cell can be continued or stopped.
7. Initially saline and then blood is re-infused into the subject via combination of peristaltic pump (8) and syringe (5). The two pump mechanisms operate at the same rate such that blood is moved along the right side (9) of the circuit only. Note, blood does not substantially progress up the left side (2) of the circuit but is re-infused past junction (10) and into the patient.
8. One or more weight scales (not shown) can be used to measure the waste and saline solution together or independently. Such weight scales can allow real time compensation between the pumps, e.g., to ensure that the rates match, or to ensure that a desired rate difference or bias is maintained. For instance it can be desirable that a certain volume of saline be infused into the patient during a recirculation cycle. In such an application, the combined weight of the waste and saline bag should decrease by the weight of the desired volume of saline. If the weight or weights do not correspond to the expected weight or weights, then one or both pumps can be adjusted. If a net zero balance is required then the combined weight at the start of recirculation mode and at the end of recirculation mode should be the same; again, one or both pumps can be adjusted to reach the desired weight or weights.
Subsequent Blood Sampling. For subsequent samples, the blood residing in the catheter (12) and extension tubing (11) has already been tested and can be considered a “used” sample. The example embodiment of
1. Syringe pump (5) and peristaltic pump (8) initiate the blood draw by drawing blood up through the right side of the blood loop.
2. The withdrawal continues until all of the used blood has passed junction (10). The volume determination made during the initial draw can enable the accurate determination of the location of the used blood sample.
3. Once the used sample has passed the junction (10), the peristaltic pump (8) can be turned off and blood withdrawn via the left side (2) of the circuit. Sensor measurement of the blood can be made during this withdrawal.
4. The withdrawal process can continue for a predetermined amount of time. Following completion of the sensor sampling (or overlapped in time), the blood can be re-infused into the patient. The blood is re-infused into subject via combination of peristaltic pump (8) and syringe pump (5). The two pumps operate at the same rate such that blood is moved along the right side (9) of the circuit only. Note, blood does not progress up the left side (2) of the circuit but is re-infused past junction (10) and into the patient. There is no requirement that the withdrawal and infusion rates be the same for this blood loop system.
Cleaning of system and saline calibration procurement. A cleaning and calibration step can clean the system of any residual protein or blood build-up, and can characterize the system; e.g., the performance of a measurement system can be characterized by making a saline calibration reference measurement, and that characterization used in error reporting, instrument self-tests, and to enhance the accuracy of blood measurements. The cleaning process can be initiated 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 performance characterization indicates that cleaning is required, or some combination thereof. A cleaning cycle can be provided with the example embodiment of
1. The start condition for initiation of the cleaning cycle 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 closed.
4. Syringe pump (5) pushes saline toward 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 arms for the loop at equal rates and the blood present in the system is re-infused into the patient.
5. Following completion of the saline infusion, both arms of the loop system (2, 9) as well as the tubing (11) and catheter (12) are filled with saline.
6. Pinch valve (42) is closed and peristaltic pump (8) is turned on in a vibrate mode or pulsatile flow mode to completely clean the loop.
7. Pinch value (42) is opened. Syringe begins pull at a third rate and peristaltic pump pulls saline at fourth rate equal to one half of the third rate. This process effectively fills the entire loop with blood while concurrently placing the saline used for cleaning into the syringe (5). Sensor measurements can occur after the blood/saline junction has passed the measurement cell.
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 and back to measurement mode.
Characteristics of the example embodiment. The example embodiment of
Example Embodiment Comprising a Blood Loop System with a Peristaltic Pump.
Push Pull System.
Push Pull System with Two Peristaltic Pumps.
Blood Sample and Measurement Process—First Sample Draw.
1. Pump (1) initiates a draw of blood from the catheter (12).
2. The blood interacts with the sensor measurement cell (2). The volume of the catheter (12) and tubing (11) can be determined and used for future reference and for the determination of blood-saline mixing.
3. Sensor measurements can be made as the blood moves through the measurement cell.
4. Pump (1) changes direction and sensor measurements continue.
5. Pump (1) reinfuses blood into the patient. As the mixed blood-saline junction passes the junction (13), it becomes progressively more dilute.
6. Following re-infusion of the majority of the blood, peristaltic 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 can be washed with saline after each measurement if desired.
8. Additionally the system can go into an agitation mode that fully washes the system
9. Finally the system can enter into a keep vein open mode (KVO). In this mode a small amount of saline is continuously or periodically infused to keep the blood access point open.
Blood sample and measurement process—Subsequent Blood Sampling. For subsequent samples, the tubing between the patient and the pump (1) is filled with saline and it can be desirable that this saline not become mixed with the blood. This can be achieved with operation as follows:
1. Pump (1) initiates the blood draw by drawing blood up through junction (13).
2. The withdrawal continues as blood passes through the sensor measurement cell (2). The blood after passing the measurement cell can be effectively stored in the tubing reservoir (5).
3. Sensor measurements can be made during this withdrawal period.
4. Following 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 period.
6. As the mixed blood-saline passes through the junction (13), it becomes progressively more dilute.
7. Following re-infusion of the majority of the blood, peristaltic pump (3) is turned on at a rate that matches the rate of pump (1). The 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 agitation mode. In this mode the fluid is moved forward and back such that turbulence in the flow occurs.
10. Between blood samplings, the system can be placed in a keep vein open mode (KVO). In this mode a small amount of saline can be infused to keep the blood access point open.
Characteristics of Push Pull with Peristaltic Pumps. The example embodiment of
Push Pull System with Syringe Pump.
Blood Sample and Measurement Process—First Sample Draw.
1. Syringe pump (5) initiates a draw.
2. The blood interacts with the sensor measurement cell (1). The volume of the catheter (12) and tubing (11) can be determined and used for future reference and for the determination of blood-saline mixing.
3. Sensor measurements can be made as the blood moves through the measurement cell.
4. The syringe pump changes direction and sensor measurements can continue.
5. Blood is re-infused into the patient. As the mixed blood-saline junction passes the junction (13), it becomes progressively more dilute.
6. Following re-infusion of a portion (e.g., the majority) of the blood, peristaltic 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 measurement if desired.
8. Additionally the system can go into an agitation mode that fully washes the system.
9. Finally the system can enter a keep vein open mode (KVO). In this mode a small amount of saline is infused to keep the blood access point open.
Blood sample and measurement process—Subsequent Blood Sampling. For subsequent samples, the tubing between the patient and the syringe is filled saline and it can be desirable that this saline not become mixed with the blood. The pinch valves enable the saline to be pushed to waste and the amount of saline/blood mixing to be minimized. This can be achieved with operation as described below.
1. Syringe pump (5) initiates the blood draw by drawing blood up through junction (13).
2. The withdrawal continues until blood saline juncture reaches the base of the syringe. At this point in the sequence, pinch valve (42) is closed and valve (41) is opened, and the syringe pump direction reversed. This process enables the resident saline to be placed into the waste bag.
3. Valve (42) is opened, valve (41) closed and the syringe is now withdrawn so that only blood or blood with very little saline contamination is pulled into the syringe.
4. Sensor measurements can be made during this withdrawal period.
5. Following completion of the blood withdrawal, the blood is re-infused into the patient by reversing the direction of the syringe pump. As the mixed blood-saline passed through the junction (13), it becomes progressively more dilute.
6. Following re-infusion of the majority of the blood, peristaltic pump (6) is activated with the concurrent infusion from the syringe pump 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 saline.
8. Additional system cleaning is possible through an agitation mode. In this mode the fluid is moved forward and back such that turbulence in the flow 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 point open.
Characteristics of Push Pull with Syringe Pump. The system can operate with little blood loss since the majority 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 infusion. The pressure monitor can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access system. The system can compensate for different size catheters through the volume pulled via the syringe pump.
The system can detect partial or complete occlusion with either the analyte sensor or the pressure sensor. An occlusion can be cleared through a variety of means. For example if the vein is collapsing and the system needs to re-infuse saline either the syringe pump or the flush pump can be 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 activated such that significant fluid can be flushed through the system for effective cleaning. In addition to high flow rates the bidirectional pump capabilities of the pumps can be used to remove occlusions.
The syringe pump mechanism can also have a source of heparin or other anticoagulant attached through an additional port (not shown). The anticoagulant solution can then be drawn into the syringe and infused into the patient or pulled through the flush side of the system. The ability to rinse the system with such a solution can be advantageous when any type of occlusion is detected.
If a microembolus 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 filled but does not initiate additional blood withdrawals. In the case of microemboli detection, the system has effectively managed the potentially dangerous situation and the nurse can be notified to examine the system for emboli formation centers such as poorly fitting catheter junctions.
Push Pull System with Syringe & Peristaltic Pump.
Blood Sample and Measurement Process—Sampling Process.
1. The passive reservoir is not filled and valve (41) is open.
2. Peristaltic pump (4) & pump (2) initiate the blood draw. The saline in the line moves into the saline bag.
3. As the blood approaches the syringe, pump (4) stops and valve (41) closes. The blood now moves into the passive reservoir.
4. Sensor sampling of the blood occurs in sensor (1).
5. Pump (2) reverses direction and the blood is infused into the patient.
6. The reservoir goes to minimum volume, at which point valve (43) opens and saline washes the reservoir and is used to push the blood back to the patient.
7. As the mixed blood-saline passes through the junction (13), it becomes progressively more dilute.
8. Following re-infusion of the majority of the blood or all of the blood, peristaltic pump (4) is turned on at the same rate as pump (2) and valves (45) and (43) are open. The combination of pumps creates a wash circuit that cleans the system.
9. Further washing of the syringe reservoir can occur by opening valves (43, 41) with pump (4) active.
10. Keep vein open infusions can occur by having pump (2) active with valve (43) open.
Characteristics of the Push Pull System with Syringe and Peristaltic Pump. Blood is always moving either into or out of the access system. Circuit cleaning can be independent of syringe cleaning. 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 of saline into waste and the fact that the mixing period is only during infusion. Saline mixing during blood infusion only. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access system. The system can compensate for different size catheters through the volume pulled via the syringe pump.
The system can detect partial or complete occlusion with either the analyte sensor or the pressure sensor. An occlusion can be cleared through a variety of means. For example if the vein is collapsing and the system needs to re-infuse saline via either syringe pump. If there is evidence of occlusion in the measurement cell area, the both syringe 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 of the pumps can be used to remove occlusions. The flexibility of the described system with the various pinch valves allows one to identify the occlusion location and establish a proactive cleaning program to minimize further occlusion.
The syringe pump mechanism can also have a source of heparin or other anticoagulant attached through an additional port (not shown). The anticoagulant solution can then be drawn into the syringe and infused into the patient or pulled through the flush side of the system. The ability to rinse the system with such a solution could be advantageous when any type of occlusion is detected.
Push Pull 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. Once a sufficient 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 desired blood property (e.g., the concentration of glucose in the blood). The pump (3) can draw saline from the bag (4) to push the blood through the system. Blood from the sensor (1) can be pushed to the waste container (18) or channel, or can optionally be returned to the patient via the optional return path (22). The transport of fluid through from the left side (2) to the right side (9) of the system can be used to clear undesirable fluids (e.g., blood/saline mixtures that are not suitable 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 is drawn from patient into the left side (2) or transported to the right side (9) of the system; and to prevent blood/saline mix and saline from the left side (9) of the system from being infused into the patient.
Push Pull with Additional Path.
Push Pull with Additional Path.
Blood Sample and Measurement Process.
1. Blood is removed from the patient via the blood pump (1) while pinch valve (44) is open and pinch valve (43) is closed.
2. At the end of the draw blood is diverted into the tubing path containing the measurement cell (9) by activation of pump (2) with the concurrent closure of pinch valve (43).
3. A volume of blood appropriate for the measurement can be pulled into (or past as needed) glucose sensor (9) and into tubing (5). The rate at which the blood is pulled into tubing (5) can be performed such that the draw time is minimized.
4. At this juncture the re-infusion process can be initiated. Pump (2) initiates a re-infusion of the blood at a rate consistent with the measurement of the blood sample. In general terms this rate is slow as the blood simply needs to flow at a rate that results in a substantially constant sensor sampling. Concurrently, pump (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 cleaned via the use of the two pumps (1, 2) as well as pinch valves (43, 44).
Characteristics of Push Pull with Additional Path. This example embodiment can perform measurement and infusion concurrently. In the previously-described push-pull system the withdrawal, measurement, and re-infusion generally occur in a sequential manner. In the system of
In addition to the reduction in total cycle time, the system has the ability to provide independent cleaning paths. By closing or opening the pinch valves in combination with the two pumps, the system can create bi-directional flows and clean the sensor measurement cell independent of the rest of the circuit. Such independent cleaning paths are especially useful when managing either complete or partial occlusions.
The push pull with additional path system as illustrated in
The push pull with additional path system as illustrated in
Sample Isolation at the Arm with Subsequent Discard.
Blood Sample and Measurement Process.
1. The blood is withdrawn 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 undiluted and clean blood sample in catheter (3).
3. Valve (4) is activated into an open position such that a small sample of blood is diverted into tubing pathway (5). The blood is subsequently transported to measurement cell (6) for measurement. The blood transport 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 re-infusion of the blood the system can be cleaned with saline by activation of pump (7).
5. The blood located in the measurement cell is measured and subsequently discarded to waste (not shown).
The system can be operated in several different modes. 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 fluids that can otherwise tend to dilute the sample. In this measurement method the volume of the sample does not need to be tightly controlled and the measurement system measures the glucose (mg/dl) in the sensor cell.
An alternative approach involves either reproducible control of the volume of blood or determination of the volume of blood and integration of the total amount of glucose measured, as illustrated in
Characteristics of Sample Isolation at the Arm with Subsequent Discard. The total amount of blood removed during the sampling process is minimized by this system. Additionally the amount of saline infused is also minimized.
The pressure needed to withdrawal the blood sample can be monitored for partial or complete occlusion. If such a situation is observed the flush pump 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 pump in conjunction with the hydraulic syringe can be used to create rapid flows, turbulent flows and to isolate particular components of the circuit for cleaning.
Sample Isolation System.
In operation, the sample system (38) draws blood from the patient into fluid transport apparatus (51) and (52). After a sufficient volume of blood has been drawn into (51) and (A2), the sample system (38) pushed blood from (52) through one-way device (32) to junction (33). Drive system (39) pushes a “plug” into junction (33), where a plug can comprise a quantity of a substance relatively immiscible with blood and suitable for transport through tubing or other components in transport apparatus (54) and suitable for transport through sensor (49) without contamination of the sensor (49). Examples of suitable plug materials include air, inert gases, polyethylene glycol (PEG), or other similar materials. An alternative type of plug can comprise fixing or clotting the blood at the leading and trailing edges. Specifically, glutaraldehyde is a substance that causes the hemoglobin in the red blood cell to become gelatinous. The net result is a gelatinous plug that can be used effectively to separate the blood used for measurement from the surrounding fluid. After the initial plug is pushed into junction (33), sample system (38) pushes additional fluid into (52), forcing blood from (53) past junction (33) forcing the initial plug in front of the blood into transport apparatus (54). Sample system can push blood into (52), or can push another suitable fluid such as saline into (52), or can reduce the volume of (52), or any other method that moves the blood in (B) into junction (33) and transport apparatus (54). Once a sufficient quantity of blood is present in transport apparatus (54), drive system (39) can push a second or trailing plug into junction (33). Transport system (39) can then push the plug-blood-plug packet through transport apparatus (54) so that the blood can be measured by sensor (49). The blood can be immediately pushed to waste (45), or pushed to waste by the transport of a subsequent sample. Since the blood in transport apparatus (54) is surrounded by relatively immiscible plugs, and since the drive system (39) can push the plug-blood-plug packet using techniques optimized for transport (e.g., pressurized air or other gas, or mechanical compression of transport apparatus (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 medium.
Sample Isolation Though Use of Air Gaps.
Blood Sample and Measurement Process.
1. Blood is withdrawn from the patient utilizing the blood pump until a clean or uncontaminated sample has been pulled pass the recirculation junction.
2. Additional blood is withdrawn from the patient by activation of the pump labeled recirculation pump. Blood is pulled to the air junction.
3. An air plug is created by pulling back on the air pump (39). The one-way valve at the air intake allows air into the tubing set for the formation of a small air gap.
4. The air gap is infused through valve (34) to create a leading air gap in junction (33) which is located at the leading edge of the uncontaminated blood sample.
5. The recirculation pump (48) then withdraws blood from the patient until an appropriate volume of uncontaminated blood has been procured.
6. The air pump (39) is again operated in the mode to create a second air gap that will be used as a trailing air segment.
7. The second air plug is infused through valve (34) to create a following air gap.
8. The blood residing in the line leading to the blood pump is infused into the patient.
9. The blood sample with leading and trailing air gaps is now transported over to the glucose sensor (45). Once in contact with the glucose sensor, an accurate glucose measurement can be made.
10. Following completion of the measurement sample is discarded to waste (45).
11. The circuit is now completely filled with saline and additional cleaning the circuit can be performed.
Characteristics of sample isolation by leading and trailing air gaps. There are a number of advantages associated with this isolation system, specifically the total amount of blood removed from the patient 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 amount of blood to the measurement site. The fact that a small amount of total blood is withdrawn results in decreased overall measurement time or dwell time. The decreased amount of blood removed enables the system to operate at lower overall withdrawal rates and with lower pressures. Additionally, the isolation the blood sample has the advantage at the isolated sample can be measured for a prolonged period of time, can be altered in ways that are incompatible with reinfusion into the patient. Due to pressure monitoring on the blood withdrawal and the possible inclusion of a second pressure sensor on the recirculation side of the circuit (not shown), the circuit design has extremely good occlusion management capabilities. The isolation of the blood sample and inability to re-infuse the sample due to the use of one-way valves, can create the opportunity to use non-sterile measurement methodologies.
Hematocrit Influence on Withdrawal Pressures.
Hematocrit Influence on Blood Saline Junction.
Use of Blood/Saline Transition for Measurement Predictions
As shown in
Modified Operation of Push Pull System with Two Peristaltic Pumps.
Modified operations. As shown in the preceding plots, high hematocrit blood requires a large pressure gradient but the increased viscosity of the blood results in smaller transition volumes. Lower hematocrit blood is the opposite, requiring lower pressures and larger transition volumes. In simple terms, the device can be operated to withdraw only enough blood such that an undiluted sample can be tested by the glucose sensor. Due to the lower transition volumes associated with higher hematocrit blood the amount of blood drawn can be appreciably smaller than the volume needed with lower hematocrit blood. For operation on a human subject the following general criteria can be desirable:
1) Minimize the total amount of blood withdrawn, this lowers overall exposure of blood to non-human surfaces.
2) Minimize the maximum pressure needed for withdrawal, this reduces the power requirements and pump sizes needed to move the blood.
3) Utilize the smallest tubing diameter possible, this reduces the blood volume and reduces mixing at the blood/saline 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.
Blood Sample and Measurement Process—Subsequent Blood Pump.
The example circuit shown in
1. Pump (1) initiates a blood draw by drawing blood through junction (13).
2. The withdrawal continues until enough blood has been withdrawn past the junction of junction (13) and the right side (9) of the loop such than an undiluted and appropriately sized blood segment can be delivered to the glucose sensor, as illustrated schematically in
3. As blood passes through the sensor measurement cell (2), it is stored in the tubing reservoir (16).
4. Sensor measurements can be made during this withdrawal period.
5. The blood can be moved back and forth over the sensor for an increased measurement performance (in some sensor embodiments) without the requirement for greater blood volumes.
6. Following completion of the blood measurement, the blood can be re-infused into the patient by reversing the direction of pump (1).
7. Sensor measurements can also be made during the re-infusion period.
8. As the mixed blood-saline passes through the junction (13), it becomes progressively more dilute.
9. Following re-infusion of the majority of the blood, 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 amount of saline re-infused into the patient. If operated at the same rate then there is substantially no net infusion into the patient. A small amount of residual blood mixed with the saline is taken to the waste bag (4).
10. This process results in a washing of the system with saline.
11. Additional system cleaning is possible through an agitation mode. In this mode the fluid is moved forward and back such that turbulence in the flow occurs. During this process both pumps can be used.
12. As a final step, the tubing between the junction and the patient, including the extension set (11), can be further cleaned by the infusion of saline by both the flush pump and the blood pump. The use of both pumps in combination increases the overall for flow through this tubing area and helps to create turbulent flow that aids in cleaning
13. Between blood samplings, the system can be placed in a keep vein open mode (KVO). In this mode a small amount of saline can be infused to keep the blood access point open.
Characteristics of Modified Push Pull Example Embodiment. The example embodiment of
The use of the flush line in a bidirectional mode has several distinct advantages. During the final washing the rate of flow to the extension set at reasonable pressures can be greater than those obtained by using only the blood pump. In addition to improved washing, the flush line can be used to “park” a diluted leading segment. Specifically, the initial draw can be performed by the flush pump (3) such that the blood saline junction is moved into the right side of the circuit. After the blood/saline junction has passed and an undiluted sample has progressed to the T-junction, the left side of the circuit can be activated via the blood pump and a blood segment with a better defined saline/blood boundary transported to the measurement sensor. As leuer fittings between 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.
Central Venous Operation. The ability to “park” the blood segment can be especially important when using the system on a central venous catheter (CVC). All figures in this disclosure show the use of the system on peripheral venous catheters, which typically have volumes of less than 500 μL. In the case of a central venous catheter, the volumes in the catheter can become quite large, around 1 ml, since that they can extend for up to 3 feet in the patient. This increased volume and length of tubing increases the amount of dead volume that must be withdrawn and increases the mixing at with the blood/saline boundary. Given the larger volumes preceding the undiluted blood segment, it can be desirable to “park” the blood from the CVC near the access location instead of transporting it through 7 feet of tubing to the measurement sensor. In operation, it has been found advantageous to use larger diameter tubing in the right side of the circuit and smaller diameter tubing in the left side. The use of larger diameter tubing enables a more rapid draw from the CVC line, while smaller tubing used to connect the glucose sensor has been found to minimize the total volume of blood removed from the patient.
Push Pull System with Two Peristaltic Pumps and Modified Sensor Location.
Blood sample and measurement process—Subsequent Blood Sampling. In operation the circuit shown in
1. Pump (1) initiates the blood draw by drawing blood up through junction (13).
2. The withdrawal continues as blood passes through the junction (13) until an undiluted segment of blood is present at the junction (13)
3. Pump (1) stops and pump (3) draws the undiluted segment toward the glucose sensor (2).
4. Following removal of an appropriate blood segment, pump (1) can be activated in a manner that cleans the tubing from the junction (13) to the patient and concurrently helps to push the undiluted segment to the glucose sensor (2).
5. Following completion of the glucose measurement, pump (3) can be activated such that majority of blood is re-infused into the patient.
6. At the point the majority of blood has been returned to the patient, pump (1) can be activated and the direction of pump (3) reversed such that the circuit is effectively cleaned. The small amount of residual blood mixed with the saline is taken to the waste bag (4).
7. Between blood samplings, the system can be placed in a keep vein open mode (KVO). In this mode a small amount of saline can be infused to keep the blood access point open.
Advantages of pressure measurement. 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 identify occlusions in the circuit during withdrawal and infusion as well as the location of the occlusion. Additionally, the pressure sensors can be used to effectively estimate the hematocrit of the blood. The pressure transducer on the flush line effectively measures pressures close to the patient, while the pressure measurement device on the blood access line measures the pressure at the blood pump. The pressure gradient is a function of volume and hematocrit. The volume pumped is known, and thus the pressure gradient can be used to estimate the hematocrit of the blood being withdrawn.
The particular sizes and equipment discussed above are cited merely to illustrate particular embodiments of the invention. It is contemplated that the use of the invention can involve components having different sizes and characteristics. It is intended that the scope of the invention be defined by the claims appended hereto.
Embodiments that automated testing intervals The present invention comprises methods and apparatuses that can provide measurement of glucose with variable intervals between measurements, allowing more efficient measurement with greater patient safety. A method according to the present invention can comprise measuring the value of an analyte such as glucose at a first time; determining a second time from a patient condition, an environmental condition, or a combination thereof; then measuring the value of the analyte at the second time. In one embodiment, the second-time can be determined from a comparison of the analyte value at the first time with a threshold. The interval between the first time and the second time can be related to the difference between the analyte value at the first time and the threshold; e.g., the closer to the threshold, the closer the two measurement times.
In another embodiment, the second time can be determined from a prediction of the value of the analyte. For example, the patient's conditions or environmental conditions, or both, can be used to predict a time at which the analyte level will reach a threshold, and the second time determined to be a predicted time, taking into consideration the physiological model; information related to infusion of nutrients, insulin, glucose, or other substances; a linear extrapolation of previous measurements; a nonlinear curve fitting of three or more previous measurements; and certain changes in patient or environmental conditions.
In some embodiments of the present invention, a second measurement can be made when a physiologic model of the patient, considering patient conditions, environmental conditions, or a combination, predicts a glucose level that has reached a threshold value. Both high and low thresholds can be established, with symmetric or asymmetric safety margins if desired.
Some embodiments of the present invention can use an optical measurement of analyte in whole blood. Some embodiments of the present invention can use measurements of analyte in portions of blood samples after removal of substantially all the red blood cells in the portion.
Such apparatuses can comprises a fluid access system, adapted to withdraw a sample of a bodily fluid such as blood from a patient; an analyte measurement system, adapted to measure the value of an analyte such as glucose concentration from the blood sample; and a controller, adapted to cause the fluidics system to withdraw a fluid sample for measurement at times determined by patient conditions, environmental conditions, or a combination thereof.
All variations can be used with automated measurement systems, allowing the system determine measurement times and automatically make measurements at the determined times, reducing operator interaction and operator error.
The determination of the next measurement time can rely on any of, or a combination of, factors such as the following.
Glucose level: as the patient begins to approach the blood glucose target limits the rate of sampling can increase such the time outside this target range is minimized.
Rate of glucose change: if the patient's blood glucose is changing rapidly the glucose may quickly exceed a target limit.
Insulin dosing history: the insulin dosing history will influence the expected rate of change and the level of blood glucose.
Caloric intake history: the caloric intake history will influence the expected change and magnitude of the blood glucose.
Medications: medications can influence the body's regulation of blood glucose and response to insulin.
Insulin sensitivity: insulin sensitivity is a general measure of the body's response to insulin dosing.
Target glucose range: the lower and tighter the range the more difficult it can be to maintain the patient's blood glucose level within this target range.
Duration of time in the intensive care unit: upon admission to the intensive care unit most patients will have a high glucose level with an initial therapy goal of getting the patient in the target range.
Model based parameters, estimated states and state predictions: The response of the glucose level to the factors noted above can be mathematically modeled to estimate model parameters and states. Such models include a) a model based on the interactions illustrated in the Netter diagram, (b) an AIDA model, (c) a Chase model, (d) a Bergman model, (e) a compartment model with differential equations, (f) an insulin pharmacokinetics and distribution model, (g) a glucose pharmacokinetics and distribution model, (h) a meal model, (i) a glucose/insulin pharmacodynamic model, and (j) an insulin secretion and kinetics model, or (k) a combination of two or more of the preceding.
The next sampling time can be determined as an interval from the previous sampling time.
The particular sizes and equipment discussed above are cited merely to illustrate particular embodiments of the invention. It is contemplated that the use of the invention can involve components having different sizes and characteristics.
Embodiments of Semi-Automated Glucose Management System An embodiment of the present invention is a semi-automated glucose management system, comprising a glucose measurement system, adapted to measure the glucose level in a patient's blood, or an indicator thereof; an infusion recommendation system, adapted to recommend infusion parameters based on information comprising the measured blood glucose level; an infusion control system, adapted to infuse glucose or insulin into the patient, and means for a clinician to authorize an infusion of glucose or insulin into the patent by the infusion control system based on a recommendation of infusion parameters by the infusion recommendation system. The glucose measurement system, infusion recommendation system, and infusion control system can be integrated in a single unit. The glucose management system can further comprise means for automated record keeping for blood glucose level measurements, glucose and insulin infusion parameters, identity of the authorizing clinician, and the timing of blood glucose level measurements and infusion parameters.
The present invention can comprise apparatuses useful for automatically determining analyte values such as blood glucose levels. Such apparatuses can comprises a fluid access system, adapted to withdraw a sample of a bodily fluid such as blood from a patient; an analyte measurement system, adapted to measure the value of an analyte such as glucose level from the blood sample; and a controller, adapted to cause the fluidics system to withdraw a fluid sample for measurement at times determined by patient conditions, environmental conditions, or a combination thereof.
The information of the infusion recommendation system can further comprise previous values of the patient's blood glucose level, the patient's previous response to previous glucose or insulin infusion, or the patient's glucose treatment characteristics.
The infusion recommendation system can further be used as a glucose measurement recommendation system. It can comprise an imbedded algorithm to recommend the infusion parameters. The clinician can vary the infusion of glucose or insulin from the recommendation of the infusion recommendation system only if a certain clinician authorization level is provided.
The glucose management system can also provide for automated record keeping. For example, an electronic or paper log can be created, with information such as glucose measurements, infusion parameters, infusion recommendations, identity of the authorizing clinician, and times of various events. The authorization system comprises means for the clinician to communicate remotely with the infusion recommendation system or the infusion control system.
The infusion control system can comprise an IV infusion pump.
Embodiments to manage cross-contamination in blood samples drawn from a multi-lumen catheter A computational fluid dynamics investigation was performed to more fully understand the potential for cross-contamination. The investigation used reasonable variations of several variables to examine the potential for cross-contamination. Variables examined and varied within reasonable limits were normal physiology flow rates in both the inferior and superior vena cava, typical intravenous infusion rates of 5% dextrose solutions, typical catheter port separation distances, and blood withdrawal rates. The investigation concluded that under the conditions investigated there was no reasonable potential for cross-contamination to occur. An identified limitation of the investigation was the relationship of the port to the wall of the vessel. Specifically, if the catheter is resting in the bottom of the vessel and the port is located on the bottom of the catheter, the flow characteristics surrounding the port would be quite different than in the center of the vessel as modeled in the computational fluid dynamics investigation.
A laboratory experiment was performed to investigate variation in flow rates and variations in catheter orientation.
System verification. The conductivity meter was tested in both the installed and uninstalled conditions. While installed, it underreported the conductivity of the solutions sampled by a factor of 0.692. Because all of the conductivity measurements taken during testing were with the sensor installed in the system, the final cross-contamination values should not be affected. If desired, the true conductivity values can be obtained by multiplying all of the ppm readings by a factor of 1.45. All of the conductivity values presented in this description are the uncorrected numbers.
To verify that the system worked as intended, infusion and withdrawal ports were switched to purposely cause cross-contamination. A 3% potassium chloride solution was infused on the proximal port 321, and the sample was withdrawn from the distalport 322 at a rate of 60 ml/hr. Flow velocity profile 1 was used. The infusion rate was increased in steps of 200, 400, 600, 800, and 999 ml/hr. The results are presented in Table 1 and
The verification data shows that sample contamination increases as infusion rate increases, verifying that the laboratory system works as expected when contamination is known to be present. The expanding range of minimum and maximum values might be due to turbulence caused by higher infusion rates. The percentage of cross-contamination was calculated using the following function:
This function can also be used to calculate the minimum detectable level of cross-contamination. Inserting the measured concentrations of the simulated blood and infused fluid, and with the minimum detectable sample concentration rise of 10 ppm
Experimental Design. Several sets of experiments were conducted to measure the cross-contamination during operation. The parameters were chosen in an attempt to increase cross-contamination as testing progressed. Infusion rates from 200 ml/hr to 999 ml/hr were tested. The concentration of the infused fluid was increased to 4% (uncorrected measurement of 27200 ppm) in order to increase the sensitivity in measured contamination levels. In addition, a test was performed with an Intralipid 20% solution consisting of about 10% potassium chloride (uncorrected measurement of 61000 ppm).
Table 2 presents the results of the experiments with an infusion fluid of KCL and water.
Table 3 presents the results of the experiments with an infusion fluid of KCL and 20% Intralipid
There was no detectable cross-contamination during any of the tests. Calculating the minimum detectable contamination with the 4% (uncorrected measurement of 27200 ppm) solution, and assuming a detectable rise in 10 ppm, gives:
And the minimum detectable contamination with the 10% (uncorrected measurement of 61000 ppm) solution gives:
Therefore, the level of cross-contamination is below 0.037% in the KCl-water tests, and below 0.017% in the KCl-Intralipid testing. The laboratory testing demonstrated that the potential for cross-contamination is very low during typical use, and in experiments depicting cases worse than the typical operating conditions, cross-contamination was less than the detectable level of 0.017%.
Animal testing. A cross-contamination study on a mechanically ventilated pig was conducted to complete the investigation into cross-contamination. The protocol for investigation was (1) Place the catheter and confirm location by fluoroscopy; (2) Evaluate flow characteristics by injecting contrast agent; (3) Evaluate for cross-contamination; (4) Move catheter to next location. The testing procedure was
1. Initiate a sampling period where blood samples are acquired from the catheter every 4 seconds, as in
2. The initial phase establishes a baseline glucose level, as shown in
3. Initiate an infusion of 50% glucose at a rate of 1000 ml/hr for a duration of 20 seconds, as shown at the start of infusion in
4. Continue acquiring samples for the duration of the infusion and for a period of 50 seconds after infusion stopped.
5. Measure the glucose levels in the samples obtained.
Evaluation of Results. In a condition without cross-contamination, the initial glucose levels and those during glucose infusion will be approximately equivalent until the infused glucose has circulated in the vascular system. The amount of infused glucose will result in approximately a 50 mg/dl systemic change assuming a total blood volume of 5 liters. This end of study glucose level will be referred to as the ending glucose level.
If cross-contamination occurs as a result of the infused glucose then the measured glucose will increase concurrently with the start of the glucose infusion. The use of a 50% glucose solution results in a significant glucose change even when the percentage of cross-contamination is less than 1%.
Four of the seven locations resulted in cross-contamination greater than 0.1%. This contrasts with the results anticipated and obtained from the computational fluid dynamics study and the laboratory investigation.
Mechanism for cross-contamination. As discussed in conjunction with
The normal venous pulse (Jugular venous pulse, JVP) reflects phasic pressure changes in the right atrium and consists of three positive waves and two negative troughs. In considering this pulse it is useful to refer to the events of the cardiac cycle. The positive presystolic “a” wave is produced by right atrial contraction and is the dominant wave in the JVP particularly during inspiration. During atrial relaxation, the venous pulse descends from the summit of the “a” way. Depending on the PR interval, this descent may continue until a plateau (“z” point) is reached just prior to right ventricular systole. More often the descent is interrupted by a second positive venous wave, “c” wave, which is produced by a bulging of the tricuspid valve into the right atrium during right ventricular isovolumic systole and by the impact of the crowded artery adjacent to the jugular vein. Following the summit of the “c” wave, the JVP contour declines, forming the normal negative systolic wave, the “x” wave. The “x” descent is due to a combination of atrial relaxation, the downward displacement of the tricuspid valve during right ventricular systole, and the ejection of blood from both the ventricles.
In the case of abnormal cardiac function, at least three mechanisms are known to cause a retrograde flow: tricuspid valve regurgitation, increased flow resistance out of the right atrium, and atrial fibrillation. In the case of tricuspid regurgitation, the right ventricle contracts but the tricuspid valve does not prevent retrograde flow into the right atrium and subsequently the thoracic veins. Possible conditions of retrograde flow can be associated with larger than normal “a” waves. Giant “a” waves are present with each beat, the right atrium is contracting against an increased resistance. This may result from obstruction at the tricuspid valve (tricuspid stenosis or atresia), right atrial myxoma or conditions associated with increased resistance to right ventricular filling. Abnormally large “a” waves can occur in patients with pulmonary stenosis or pulmonary hypertension in whom both the atrial and right ventricular septa are intact. Abnormally large and typically narrow “a” waves, often referred to as Cannon “a” waves, occur when the right atrium contracts while the tricuspid valve is closed during right ventricular systole. Cannon waves can occur either regularly or irregularly and are most common in the presence of arrhythmias. Atrial fibrillation is a condition known to cause the irregular occurrence of cannon “a” waves.
Another known source of stagnant or retrograde flow is mechanical ventilation. During normal breathing the diaphragm is lowered creating a negative pressure in the thoracic cavity. This negative pressure creates the gradient for air movement and for the filling of the lungs with each new breath. The negative pressure in the thoracic cavity also helps blood return to the heart. In the case of positive pressure ventilation, the pressure gradients are reversed. As shown in
In the study animal conducted, reverse flow occurred during the periods of positive pressure ventilation. To help confirm that mechanical ventilation is the major source of retrograde flow and subsequent contamination, one location was examined with and without ventilation. For the catheter location in the mid abdomen, two tests were conducted. The first was conducted with mechanical ventilation on and the second test with no ventilation. The rate of ventilation was 10 breaths per minute. As can be seen by comparing
Detection of cross-contamination. Reliable detection of conditions that are likely to lead to cross-contamination can be beneficial, since glucose measurements made during such conditions can be adjusted or discarded as possibly inaccurate. Pressure changes can be used to detect conditions likely to lead to cross-contamination. The measured glucose values can themselves be used to detect when one or more measured values are likely to have been compromised by cross-contamination. The physics describing the potential for cross-contamination indicate that the amount of cross-contamination can be sensitive to the withdrawal rate. Cross-contamination can be detected by comparing two different analyte values. Cross-contamination can be assessed by making two measurements where the difference between the measurements is the operation of the infusion pumps.
Reducing the influence of cross-contamination. It can be convenient for a measurement system to automatically adjust its operation to reduce the influence of cross-contamination. As one example, if the measured response shows variations in glucose values that are consistent with the ventilation frequency then the resulting data stream can be processed to remove the values likely to be influenced by cross-contamination. In a simple example, the lowest 10% of values in a sequence of measurement values can be averaged and this number be reported as the measured glucose value. More sophisticated process methods such as digital filtering or Fourier transformation can also be used.
Under conditions where the patient is not ventilated or the influence of ventilation is moderately small, the withdrawal rate can be a more important factor. In the animal testing conducted with catheter locations near the right atrium or in the pelvis, there was no appreciable cross contamination but the withdrawal rate was only 20 ml/min. A nurse can easily generate withdrawal rates in excess of 60 ml/min. The potential for cross-contamination is influenced by the flow rate of blood at the site of the central venous catheter, the rate of infusion, the rate of withdrawal, the glucose concentration of the infused fluid, catheter port orientation and the distance between the point of infusion and withdrawal. The rate of withdrawal is an important parameter in determining cross-contamination: control of this parameter can reduce the likelihood of cross-contamination. In the hospital environment the rate of withdrawal can vary appreciably due to the type of syringe used, the force applied by the nurse or clinical care provider, and a variety of other uncontrolled variables. Under a variety of conditions, the withdrawal rate of the blood access system can specified and controlled such that the amount of cross-contamination does not affect the clinical efficacy of the device. Based upon medical data, the typical flow in a non-ventilated patient in the superior vena cava will average between 10 and 20 cm per second with a peak at 35 cm per second in the direction towards the heart. This will overwhelm both the infusion velocity and the withdrawal velocity of the infused drugs except for periods of about 200 ms during which the flow is retrograde at about one to 2 cm per second for about 150 ms. The retrograde flow will cause the infused fluid from the medial port to move in a retrograde manner over a distance of about 0.3 cm. The typical distance between ports on most central venous catheters is about 1 cm. The use of withdrawal rates that do not create enough suction to pull the glucose infusion across the port separation distance should be used when procuring blood samples for glucose measurement. Cross contamination can be prevented during blood withdrawal by interrupting the withdrawal of the sample during the inflation of the lung or at any point where cross-contamination is sufficiently likely. As noted previously, the large venous vessels in the thoracic cavity do not have valves, therefore flow is determined by pressure gradients. For the purposes of determining the presence of reverse flow, measurement of intravascular pressures or pressure changes can be beneficial. In the blood access circuit shown in
In practice, it can be desirable to minimize the total time needed to withdraw the blood and eliminate any unwanted flow characteristics at the catheter tip due to the overall compliance of the circuit. These desired requirements can be achieved with responsive and active control of fluid flows, pressures, or a combination thereof. Four methods of interrupting flow for the purpose of anti-cross contamination controls have been identified: 1) a compliance isolation method, 2) a flow feedback method 3) a cascade pressure-flow feedback control method and 4) a pressure feedback method. For completeness of the description of operation, the block diagrams of these example circuits include direct measurement of the ventilator stage and include the determination of lag between the ventilator stage and the intravascular pressure change, although as described herein variations are possible.
Compliance Isolation: The compliance isolation method provides anti-contamination control by using pinch valves that close fluid connections between the pump loop tubing and the sensor set at the blood optionally and optionally the flush pump, interrupting flow during the interval of lung inflation. This method works with the example pressure based withdrawal technique shown and prevents or minimizes flow reversal during the intervals of interruption by isolating the soft compliance of the pump loops from the stiffer portions of the sensor set. The pinch valves are activated immediately upon the signal of lung inflation and the pumps are allowed to continue operating at the pressure target with zero flow. Any alarms that would normally sense occlusions during the withdrawal can be deactivated during this interval.
As shown in
Flow Feedback Control:
For this method to work properly, the desired flow target must be set at a value that does not cause pressure to exceed the pressure limit beyond which degassing of the fluids might be expected to occur. Pressure can increase as additional blood is drawn into the blood line so the flow target must be set so that pressure is maintained within the limit at the end of the draw. The desired flow target command shaping and timing are determined according to a flow reference trajectory generator that determines the latency between the ventilator pressure signal and ventilator induced pressure changes on the blood pressure measurement. These latencies are determined during KVO and used to delay the command to stop flow accordingly.
Cascaded Flow-Pressure Feedback Control: The cascade control method enhances the benefits of 1) maximum draw rate at a target negative upstream pressure which limits the de-gas rate of fluids during intervals where cross contamination is not expected, and 2) rapid deceleration of fluid flow rate to zero (or near zero) during intervals where cross contamination is expected. These benefits are achieved by using an inner, flow feedback control loop, and an outer, pressure feedback control loop. These inner and outer loops comprise the control cascade.
The inner flow feedback loop is operational all the time during the draw as well as draw interruptions, and the outer pressure feedback loop is only active between the flow interruptions. The inner flow feedback loop effectively stiffens the flow impedance of the sensor set. This results in a faster time constant in the flow response as compared to the sensor set without flow feedback where changes in flow rate are limited by the intrinsic compliance and resistance of the sensor set.
The outer pressure feedback loop provides the command signal to the inner flow feedback loop during the interval of lung deflation, where cross contamination is not expected to occur. The pressure loop targets a high negative pressure during that interval to maximize the draw rate however within a pressure constraint that prevents or minimizes degassing of the blood and maintenance fluid. During lung inflation the pressure controller is reset and held inactive with a command of zero flow to the inner flow loop.
Pressure Feedback Control: The pressure feedback control method utilizes the same pressure feedback control servo used during the draw intervals for the intervals that interrupt withdrawal by substituting a slightly positive pressure target during these intervals. This results in an immediate reversal of the pump just after the draw which prevents reversal of flow during the interrupts and maintains a slight positive flow from the canula.
To further confirm the operational principles with respect to controlling flow in a blood access circuit, a simple confirmatory test was conducted in the laboratory. A blood access circuit and pumping mechanism as shown in
The particular sizes and equipment discussed above are cited merely to illustrate particular embodiments of the invention. It is contemplated that the use of the invention can involve components having different sizes and characteristics.
Indwelling Fiber Optic Probe for Blood Glucose Measurements
The fiber optic probe can comprise various illumination and collection optical configurations comprising one or more optical fibers having flat faced or shaped ends, and external optical elements, such as micromirrors and microlenses, to optimize the illumination and collection characteristics of the sample volume. Further, the numerical aperture, core and cladding materials, geometry, size, and arrangement and number of optical fibers can be chosen to optimize the delivery of light to and from the blood sample and to enable biocompatibility of the indwelling probe. The optical fibers can be contained in a catheter that can be inserted into a patient's tissue.
The small dimensions of optical fibers allow multiple illumination and collection fibers to be bundled into a single catheter.
The optical probe can be configured to enable a background reference measurement.
An apparatus for hemodvnamic monitoring and analyte measurement The sharing of a single arterial access site for both hemodynamic monitoring as well as blood sample procurement requires attention to a variety of implementation details. In simple terms the automated measurement system should not: (1) change or influence the dynamic response of the hemodynamic monitoring system; (2) create pressure gradients that result in inaccurate measurements; or (3) introduce bubbles. Any of the above may create a situation where the hemodynamic values are inaccurate.
As shown in
Instead of providing a surrogate signal, the system also has the ability to compensate for the pressure artifact being introduced by the automated blood measurement system. Through the use of both pressure transducers as well as knowledge regarding the state of both pumps, the pressure artifact can be determined enabling the determination of the true pressure at the arterial catheter. This process enables the procurement of an undiluted blood sample to the measurement system while concurrently affording real-time hemodynamic monitoring. The ability to determine the pressure gradients being produced by the automated blood measurement system enables hemodynamic monitoring to continue during a greater portion if not all of the measurement cycle. The provision of an accurate pressure trace during the entire automated analyte measurement sequence means that the patient's hemodynamic status and associated alarm methodologies remain fully operational and active during the automated blood analyte measurement.
A volume control mechanism maintained the volume of the chamber so that the voice coil operated within its normal/linear range.
The impact of a measurement cycle on hemodynamic monitoring performance was determined. The variable pressure, variable volume system (aka the artificial patient) was attached as shown in
a. Catheter Clear: an infusion pulse to clear catheter before draw
b. Background: a first calibration point at one glucose concentration
c. Blood draw: pulls blood in to the circuit
d. Blood measurement: the period over which a measurement is made
e. Fast infuse: a stage that infuses the blood into the patient
f. Infuse/stop: a stage that infuses blood into the patient but does so by infusing and stopping, a process that improves overall cleaning
g. Calibration recirculation: a combination phase involving cleaning of the circuit in the movement of a second calibration solution to the sensor.
h. Calibration measurement: a second calibration point at a second glucose concentration.
i. Reverse recirculation: a stage to remove the second calibration solution from the sensor.
Hemodynamic monitoring disruption can be mitigated by the use of an access mechanism that provided independent or semi-independent access through a single access location. For example a dual lumen catheter could be used. For example the Arrow International TWINCATH® 20/22 multiple-lumen peripheral catheter could be used in such a situation. The catheter contains two separate non-communicating lumens.
Another mechanism that provides access via two different pathways is the use of a arterial sheath with side arm and catheter.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery. In such an example apparatus the arterial catheter can have first and second lumens, and the blood pressure measuring subsystem can be mounted in fluid communication with first lumen, and the analyte measuring subsystem can be mounted in fluid communication with the second lumen.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery. In such an example apparatus, the arterial catheter can comprise (i) a hub defining an internal volume characterized by an internal diameter and having a fluid port in fluid communication with the internal volume; and (ii) a catheter having an external diameter less than the hub internal diameter and mounted within the internal volume; and the pressure monitoring subsystem can be mounted in fluid communication with either the fluid port of the hub or the catheter, and the analyte measuring subsystem can be mounted in fluid communication with the other of the fluid port of the hub or the catheter.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery. In such an example apparatus, the analyte measuring subsystem can transport blood from the catheter; and the apparatus can further comprise an alarm and display subsystem, responsive to the blood pressure monitoring device and the analyte measuring subsystem, configured such that an alarm is indicated when both (i) the pressure monitoring subsystem indicates pressure outside a range of acceptable values and (ii) the analyte measuring subsystem indicates that the pressure monitoring subsystem indication is not invalidated by the analyte measuring subsystem.
In an example apparatus as in the preceding paragraph, the alarm and display subsystem can be further configured to display (i) an indication of pressure responsive to the pressure monitoring subsystem when the analyte measuring subsystem does not indicate interference with the pressure monitoring subsystem, and (ii) an indication that analyte measurement subsystem is interfering with the pressure monitoring subsystem when the analyte measuring subsystem does indicate interference with the pressure monitoring subsystem.
In an example apparatus as in the preceding paragraph, the indication that the analyte measurement subsystem is interfering with the pressure monitoring subsystem can comprise one or more of a text message, a change in color of the display, a change in size of a displayed waveform, or a waveform with a shape recognizably distinct from normal patient pressure waveforms.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery. In such an example apparatus, the analyte measuring subsystem can transport blood from the catheter; and the apparatus can further comprise a display subsystem, responsive to the blood pressure monitoring device and the analyte measuring subsystem, configured to display a pressure indicated by the pressure monitoring subsystem when the analyte measuring subsystem is not interfering with the pressure measurement subsystem, and to determine and display a compensated pressure measurement during times when the analyte measurement subsystem is interfering with the pressure measurement subsystem.
In an example apparatus as in the preceding paragraph, the display subsystem can determine a compensated pressure measurement according to the output of the pressure sensor and information provided by the analyte measurement subsystem.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood pressure monitoring subsystem mounted with the arterial catheter such that the blood pressure monitoring subsystem can determine the pressure of blood in the artery; and an analyte measuring subsystem mounted with the arterial catheter such that the analyte measuring subsystem can determine the presence, concentration, or both of one or more analytes in blood withdrawn from the artery. In such an example apparatus, the mechanical compliance of the combination of the pressure monitoring subsystem and the analyte measuring subsystem satisfies the Gardner wedge criteria.
A method of calibrating any of the example apparatuses described herein can comprise operating the analyte measurement system such that fluid movement during calibration does not introduce errors of more than 5% in the output of the pressure monitoring subsystem.
An example apparatus according to the present invention comprises an arterial catheter, configured to be placed in fluid communication with an artery of a patient; a blood access subsystem, comprising: an analyte measurement device; a pressure sensor; a fluid path from the arterial catheter to the analyte measurement device and to the pressure sensor; at least one pump configured to move fluid in the fluid pathways; and a control system operatively connected to the pump to control operation of the pump; and a pressure determination system responsive to the pressure sensor and to the control system, configured to determine a signal corresponding to pressure in the artery from the pressure sensor and from the characteristics of the pump as indicated by the control system.
In an example apparatus as in the preceding paragraph, the pressure determination system can determine a signal corresponding to pressure in the artery by a lumped parameter model.
An example analyte measurement apparatus according to the present invention comprises a blood access subsystem, configured to transport fluid from a fluid access port connected to an arterial catheter during defined fluid transport times; an analyte measurement subsystem, configured to determine an analyte property of said withdrawn blood; and a pressure signal communication subsystem, configured to accept an input pressure signal from a pressure measurement system in fluid communication with the fluid access port, and to output a signal determined by (i) the input pressure signal except during fluid transport times, and (ii) a determined signal during fluid transport times.
In an example apparatus as in the preceding paragraph, the determined signal can correspond to a compensated pressure signal. In an example apparatus as in the preceding paragraph, the determined signal can comprise a signal having a high value, a low value, and a frequency similar to that of the input pressure signal during times that are not fluid communication times, but that has a waveform shape that is observably different from that of the input pressure signal during times that are not fluid transport times.
In an example apparatus as in the preceding paragraph, the waveform shape can comprise a square wave, a triangle wave, a simulated pressure wave with noise added, or a combination of any of two or more of the preceding.
Calibrating an automated analyte measurement system The present invention is described herein in the context of example blood access and measurement systems, for convenience of description. The present invention can also be used in combination with other blood access systems, such as those described in the applications incorporated by reference above.
The systems shown
The system shown in
In a first example method, the invention provides a method of calibrating an automated analyte measurement system that removes blood from a patient for measurement, comprising passing calibration fluid having at least two different analyte concentrations by an analyte sensor while infusing substantially none of at least one of such calibration fluids into the patient. In such an example, that sensor and calibration fluid can be maintained in a sterile condition.
In a second example method, the present invention provides a method of validating the performance of an automated analyte measurement system, comprising calibrating the system according to the method of claim 1, then determining the sensor response to a calibration fluid having an analyte concentration different from those used in calibration while infusing substantially none of such calibration fluid into the patient.
In a first example apparatus, the present invention provides an apparatus for the measurement of one or more analytes in blood withdrawn from a patient, comprising: a patient connection fluid passage element configured to be placed in fluid communication with the vascular system of a patient; an analyte sensor having first and second ports, the first port in fluid communication with the patient connection fluid passage element; a first fluid source in fluid communication with the second port of the analyte sensor; a second fluid source in fluid communication with the first port of the analyte sensor; a first pump mounted with the apparatus so as to move fluid from the first fluid source towards or away from the analyte sensor; a second pump mounted with the apparatus so as to urge fluid from the second fluid source toward or away from the analyte sensor; and a waste outlet in fluid communication with at least one of the first and second ports of the analyte sensor; wherein at least one of the first fluid source and the second fluid source contains a fluid having a first known analyte concentration suitable for calibration of the analyte sensor.
In an apparatus like the first example apparatus, the first fluid source can contain a fluid having a first known analyte concentration suitable for calibration of the analyte sensor, and wherein the second fluid source contains a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor.
In an apparatus like the first example apparatus, the apparatus can further comprise a third fluid source in fluid communication with at least one of the first port or the second port of the analyte sensor, and containing a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor.
In an apparatus like the first example apparatus, the apparatus can further comprise a selection or mixing valve mounted between either the first fluid source or the second fluid source and the corresponding port of the analyte sensor, and further comprising a third fluid source in fluid communication with the variable mixing valve, and containing a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor.
In a second example apparatus, the present invention provides an apparatus for measurement of one or more analytes in blood withdrawn from a patient, comprising: a patient connection fluid passage element configured to be placed in fluid communication with the vascular system of a patient; an analyte sensor having first and second ports, the first port in fluid communication with the patient connection fluid passage element and separated therefrom by a fluid passage having a first length; a tubing junction comprising first, second, and third ports, the first port in fluid communication with the second port of the analyte sensor and separated therefrom by a fluid passage having a second length; a first fluid source in fluid communication with the second port of the tubing junction and separated therefrom by a fluid passage having a third length, where the sum of the second and third lengths is greater than the first length; a second fluid source in fluid communication with the third port of the tubing junction; a first pump mounted with the apparatus so as to urge fluid from the first fluid source towards or away from the tubing junction; and a second pump mounted with the apparatus so as to urge fluid from the second fluid source toward or away from the tubing junction; wherein the first fluid source contains a fluid having a first known analyte concentration suitable for calibration of the analyte sensor.
In an apparatus like the second example apparatus, the second fluid source can contain a fluid having a second known analyte concentration suitable for calibration of the analyte sensor.
In an apparatus like the second example apparatus, the apparatus can further comprise a selection or mixing valve mounted between the first fluid source and the tubing junction, and further comprising a third fluid source having a fluid having a third known analyte concentration suitable for calibration of the analyte sensor mounted in fluid communication with the selection or mixing valve.
In a third example apparatus, the present invention provides an apparatus for the measurement of one or more analytes in blood withdrawn from a patient, comprising: a patient connection fluid passage element configured to be placed in fluid communication with the vascular system of a patient; an analyte sensor having first and second ports, the first port in fluid communication with the patient connection fluid passage element; a reservoir in fluid communication with the second port of the analyte sensor; a first fluid source in fluid communication with the second port of the analyte sensor, wherein the first fluid source contains a fluid having a first known analyte concentration suitable for calibration of the analyte sensor; a first pump mounted with the apparatus so as to urge fluid from the first fluid source towards or away from the analyte sensor; and a second pump mounted with the apparatus so as to urge fluid from the reservoir toward or away from the analyte sensor.
In an apparatus like the third example apparatus, the apparatus can further comprise a second fluid source in fluid communication with the second port of the analyte sensor, wherein the second fluid source contains a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor.
In third example method, the present invention provides a method of calibrating an apparatus such as the first example apparatus, comprising operating the first and second pumps to flow fluid from the fluid source having a known analyte concentration past the sensor and to the waste outlet, and calibrating the analyte sensor responsive to its response to the fluid having the first known analyte concentration.
In a method like the third example method, wherein the apparatus further comprises a third fluid source in fluid communication with at least one of the first port or the second port of the analyte sensor, and containing a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor, the method can further comprise operating the first and second pumps to flow fluid from the fluid source having a known analyte concentration past the analyte sensor and to the waste outlet, and operating the first and second pumps to flow fluid from the third fluid source past the analyte sensor and to the waste outlet, and calibrating the analyte sensor responsive to its response to the fluid having the first known analyte concentration and its response to the fluid having the second known analyte concentration.
In a method like the third example method, wherein the apparatus further comprises a selection or mixing valve mounted between either the first fluid source or the second fluid source and the corresponding port of the analyte sensor, and further comprising a third fluid source in fluid communication with the selection or mixing valve, and containing a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor, the method can further comprise configuring the selection or mixing valve to pass either of its input fluids or a combination of its input fluids to deliver a first calibration fluid having a first calibration analyte concentration, and operating the first and second pumps to flow the first calibration fluid past the analyte sensor and to the waste outlet, and configuring the selection or mixing valve to pass either of its input fluids or a combination of its input fluids to deliver a second calibration fluid having a second calibration analyte concentration different from the first calibration analyte concentration, and operating the first and second pumps to flow the second calibration fluid past the analyte sensor and to the waste outlet, and calibrating the analyte sensor responsive to its response to the first calibration fluid and its response to the second calibration fluid.
In a method like the third example method, the method can be practiced such that substantially none of the fluid is infused into the patient. In a method like the third example method, the method can be practiced such that an amount of fluid less than the amount that would be likely to cause harm to the patient can be infused into the patient.
In fourth example method, the present invention provides a method of calibrating an apparatus such as in the second example apparatus, comprising operating the first and second pumps to flow fluid from the first fluid source past the analyte sensor while infusing into the patient a volume less than the volume defined by the fluid passage between the tubing junction and the first fluid source, and calibrating the analyte sensor responsive to its response to the fluid.
In a method like the fourth example method, wherein the second fluid source contains a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor, the method can further comprise operating the first and second pumps to flow fluid from the second fluid source past the analyte sensor while infusing into the patient a volume less than the volume defined by the fluid passage between the tubing junction and the second fluid source, and calibrating the analyte sensor responsive to its response to the fluid from the first fluid source and its response to fluid from the second fluid source.
In a method like the fourth example method, wherein the apparatus further comprises a selection or mixing valve mounted between the first fluid source and the tubing junction, and further comprising a third fluid source having a fluid having a third known analyte concentration suitable for calibration of the analyte sensor mounted in fluid communication with the selection or mixing valve, the method can further comprise configuring the selection or mixing valve to deliver a first calibration fluid comprising fluid from the first fluid source, fluid from the third fluid source, or a combination thereof, and operating the pumps to flow the first calibration fluid past the analyte sensor while infusing into the patient a volume less than the volume defined by the fluid passage between the tubing junction and the selection or mixing valve, and configuring the selection or mixing valve to deliver a second calibration fluid comprising fluid from the first fluid source, fluid from the third fluid source, or a combination thereof, and operating the pumps to flow the second calibration fluid past the analyte sensor while infusing into the patient a volume less than the volume defined by the fluid passage between the tubing junction and the selection or mixing valve, and calibrating the analyte sensor responsive to its response to the first and second calibration fluids.
In a fifth example method, the present invention provides a method of calibrating an apparatus such as the third example apparatus, comprising operating the first and second pumps to withdraw blood from the patient past the analyte sensor and into the reservoir, and operating the first and second pumps to draw blood from the reservoir and fluid from the first fluid source to present a mixture of blood from the reservoir and fluid from the first fluid source to the analyte sensor, and calibrating the analyte sensor responsive to its response to the blood and to the mixture of blood and the fluid from the first fluid source.
In a method like the fifth example method, wherein the apparatus further comprises a second fluid source in fluid communication with the second port of the analyte sensor, wherein the second fluid source contains a fluid having a second known analyte concentration, different from the first known analyte concentration, suitable for calibration of the analyte sensor, the method can further comprise operating the first and second pumps to draw blood from the reservoir and fluid from the second fluid source to present a mixture of blood from the reservoir and fluid from the second fluid source to the analyte sensor, and calibrating the analyte sensor responsive to its response to the blood and to the mixture of blood and the fluid from the first fluid source and to the mixture of blood and fluid from the second fluid source.
Method for controlling a level of blood glucose in a patient using an extracorporeal blood circuit] An extracorporeal glucose system and controller has been developed which overcomes many of the limitation of currently proposed glucose control systems by enabling the measurement of the concentration of glucose in blood with little or no delay. This affords a much faster control system while protecting the glucose sensor from contamination by blood and facilitating periodic external calibration.
The glucose maintenance apparatus includes a blood pump console 106 and a blood circuit 107. The console includes three rotating roller pumps that move blood, ultrafiltrate fluids and insulin through the circuit, and the circuit is mounted on the console. The blood circuit includes a continuous blood passage between the withdrawal line 104 and the return line 105. The blood circuit includes a blood filter 108; pressure sensors 109 (in withdrawal tube), 110 (in return tube) and 111 (in filtrate output tube); an ultrafiltrate collection bag 112 and tubing lines to connect these components and form a continuous blood passage from the withdrawal to the infusion catheters an ultrafiltrate passage from the filter to the ultrafiltrate bag, connections for the attachment of a glucose calibration solution 123 and an insulin infusion bag 128. The ultrafiltrate line 120 is connected to the glucose calibration solution 123 via the tubing 124 by a valve system facilitating the calibration sequence.
The blood passage through the circuit is preferably continuous, smooth and free of stagnate blood pools and air/blood interfaces. These passages with continuous airless blood flow reduce the damping of pressure signals by the system and allows for a higher frequency response pressure controller, which enables the pressure controller to adjust the pump velocity more quickly to changes in pressure, thereby maintaining accurate pressure control without causing instability in control. The components of the circuit may be selected to provide smooth and continuous blood passages, such as a long, slender cylindrical filter chamber, and pressure sensors having cylindrical flow passage with electronic sensors embedded in a wall of the passage. The circuit may come in a sterile package and is intended that each circuit be used for a single treatment.
The circuit mounts on the blood, insulin and ultrafiltrate pumps 113 (for blood passage) 127 for the insulin passage and 114 (for filtrate output of filter). The circuit can be mounted, primed and prepared for operation within minutes by one operator. The operator of the glucose control apparatus 100, e.g., a nurse or medical technician, sets the maximum rate at which fluid is to be removed from the blood of the patient. These settings are entered into the blood pump console 106 using the user interface, which may include a display 115 and control panel 116 with control keys for entering maximum flow rate and other controller settings.
Information to assist the user in priming, setup and operation is displayed on the LCD (liquid crystal display) 115. The operator also sets the target glucose level along with upper and lower control limits whereby the console 100 annunciates an alarm when exceeded.
The ultrafiltrate is withdrawn by the ultrafiltrate pump 114 into a graduated collection bag 112 or is returned at the outlet of the blood pump 152 to facilitate predilution of the blood before entering the filter housing 108. The valve 124 may be manually switched by the operator or controlled automatically via a rotary solenoid valve based upon. When the bag is full, ultrafiltration delivery into the bag stops until the bag is emptied. The valve 124 can redirect the ultrafiltrate liquid exiting the ultrafiltrate pump 114 enter the blood line exiting the blood pump and predilute the blood entering the filter 108. The controller may determine when the bag is filled by determining the amount of filtrate entering the bag based on the volume displacement of the ultrafiltrate pump in the filtrate line and filtrate pump speed, or by receiving a signal indicative of the weight of the collection bag. An air detector 117 monitors for the presence of air in the blood circuit, blood is pumped through the circuit. The predilution ultrafiltrate may be returned upstream of the filter and the air detector 117 to ensure that air is not infused into the patient. A blood glucose sensor 150 is connected directly to the filtrate side of the filter with the sensor inserted between the hollow membrane fiber bundles ensuring the fastest signal response possible. A second blood glucose sensor 121 is attached to ultrafiltrate line 120 and can be calibrated with the glucose calibration solution from the bag 123 when the ultrafiltrate pump 114 is reversed via a one way valve 131 (
a illustrates the operation and fluid paths of blood, insulin and ultrafiltrate through the blood circuit 107. Blood is withdrawn from the patient through the lumens 102 and 103. The catheter is inserted into a suitable vein defined by current medical practice which can sustain a blood flow of 5 to 40 ml/min. The blood flow from the withdrawal tubing 104 is dependent on the fluid pressure in that tubing which is controlled by a roller pump 113 on the console 106. The algorithms for controlling the withdrawal, infusion and ultrafiltrate pressures are disclosed in U.S. Pat. Nos. 6,796,955; 6,689,083 and 6,706,007 and are incorporated by reference herein.
The pressure sensors may also have a blood passage that is contiguous with the passages through the tubing and the ID of the passage in the sensors may be similar to the ID in the tubing. It is preferable that the entire blood passage through the blood circuit (from the withdrawal catheter to the return catheter) have substantially the same diameter (with the possible exception of the filter) so that the blood flow velocity is substantially uniform and constant through the circuit. A benefit of a blood circuit having a substantially uniform ID and substantially continuous flow passages is that the blood tends to flow uniformly through the circuit, and does not form stagnant pools within the circuit where clotting may occur.
The withdrawal pressure sensor 109 is a flow-through type sensor suitable for blood pressure measurements. It is preferable that the sensor have no bubble traps, separation diaphragms or other features included in the sensor that might cause stagnant blood flow and lead to inaccuracies in the pressure measurement.
The filter 108 is used to:
Ensure that the glucose sensors 150 and 121 are not contaminated and made inoperable by blood components larger than 50,000 daltons.
Ultrafiltrate the blood and decrease the amount of time it takes for the glucose sensor to get an accurate reading of glucose in the blood.
Remove excess fluid from the patient if necessary.
Whole blood enters the filter 108 and passes through a bundle of hollow filter fibers in a filter canister. There may be between 100 to 1000 hollow fibers in the bundle, and each fiber is a filter. In the filter canister, blood flows through an entrance channel to the bundle of fibers and enters the hollow passage of each fiber. Each individual fiber has approximately 0.2 mm internal diameter. The walls of the fibers are made of a porous material. The pores are permeable to water and small solutes, but are impermeable to red blood cells, proteins and other blood components that are larger than 50,000-60,000 Daltons. Blood flows through the fibers tangential to the surface of the fiber filter membrane. The shear rate resulting from the blood velocity is high enough such that the pores in the membrane are protected from fouling by particles, allowing the filtrate to permeate the fiber wall. Filtrate (ultrafiltrate) passes through the pores in the fiber membrane (when the ultrafiltrate pump is rotating), leaves the fiber bundle, and is collected in a filtrate space between the inner wall of the canister and outer walls of the fibers. The volume of the filter that contains the ultrafiltrate has been designed to be as small as possible and still facilitate the manufacturing of the filter. This volume acts to dampen the real time blood glucose measurements by acting as a reservoir for ultrafiltrate. To help reduce this affect, the blood glucose sensor 150 is embedded in the ultrafiltrate compartment of the filter 108 with the sensor measurement site lying within the polysulphone fibers of the filter. The membrane of the filter acts as a restrictor to ultrafiltrate flow. An ultrafiltrate pressure transducer (Puf) 111 is placed in the ultrafiltrate line upstream of the ultrafiltrate roller pump 114. The ultrafiltrate pump 114 is rotated at the prescribed fluid extraction rate which controls the ultrafiltrate flow from the filter. Before entering the ultrafiltrate pump, the ultrafiltrate passes through approximately 10 cm of plastic tubing 120, the blood leak detector 118, the ultrafiltrate pressure transducer (Puf) and the second reference glucose sensor 121. The tubing is made from medical PVC of the kind used for IV lines and has internal diameter (ID) in this case of 3.2 mm. The ultrafiltrate pump 114 is rotated by a brushless DC motor under microprocessor control. The pump tubing segment (compressed by the rollers) has the same ID as the rest of the ultrafiltrate circuit.
In this operational configuration both the control glucose sensor 150 and the reference glucose sensor measure the concentration of glucose in the blood. The reference glucose sensor 121 has an added lag and time delay due to the volume of ultrafiltrate in the filter filtrate cavity and the volume of tubing between the outlet of the filter 120 and the reference glucose sensor 121. To periodically calibrate the reference glucose sensor 121, the ultrafiltrate pump 114 is reversed. When the ultrafiltrate pump 121 is reversed (rotated anticlockwise) the one way valve 130 prevents ultrafiltrate from the ultrafiltrate bag 112 or blood from the output of the blood pump from entering the return ultrafiltrate line 170. At the same time, glucose calibration solution is drawn through a one way valve 131 connected to the ultrafiltrate line 132 at the T-connection 133. The one-way valve 131 opens due to the negative pressure generated by the reversing ultrafiltrate pump 114. The ultrafiltrate pump is only displaced the volume required to flush the ultrafiltrate line 132 and ensure that the reference glucose sensor is reading an uncontaminated reference solution, e.g., the calibration solution 123. The volume of the tubing between the calibration solution 131 and the reference glucose sensor is less than the volume between the reference glucose sensor and the outlet of the ultrafiltrate from the filter 108. This ensures that during reversal the filtrate cavity of the filter 108 is not contaminated with the glucose calibration solution. During the calibration sequence the control glucose sensor 150 relies on diffusion to measure the correct level of glucose in the blood. The sensor 150 provides an uninterrupted signal for control during the calibration sequence.
After the blood passes through the filter 108, it is pumped through a two meter infusion return tube 105 to the infusion needle 103 where it is returned to the patient. The properties of the filter 108 and the infusion needle 103 are selected to assure the desired TMP (Trans Membrane Pressure) of 150 to 250 mm Hg at blood flows of 5 to 40 ml/min where blood has hematocrit of 35 to 48% and a temperature of room temperature (generally 21 to 23.degree. C.) to 37.degree. C.
Insulin is also infused into the return line of 105 of the blood circuit. The measurements taken from the control glucose sensor 150 are used to calculate the rate of infusion of glucose required to keep the patients glucose between 80 and 110 mg/dl. An insulin solution is withdrawn from the insulin solution bag 128 and pumped through an air detector 126 before being infused into the return line 105 via the T-connector 171. This configuration is shown with a peristaltic pump 127 but could be replaced with an infusion syringe pump. The pump 127 controls the rate of insulin injection. The controlled insulin rate is determined based on the measured glucose level.
The blood leak detector 118 detects the presence of a ruptured/leaking filter, or separation between the blood circuit and the ultrafiltrate circuit. In the presence of a leak, the ultrafiltrate fluid will no longer be clear and transparent because the blood cells normally rejected by the membrane will be allowed to pass. The blood leak detector detects a drop in the transmissibility of the ultrafiltrate line to infrared light and declares the presence of a blood leak.
The pressure transducers Pw (withdrawal pressure sensor 109), Pin (infusion pressure sensor 110) and Puf (filtrate pressure sensor 111) produce pressure signals that indicate a relative pressure at each sensor location. Prior to filtration treatment, the sensors are set up by determining appropriate pressure offsets. The offsets are determined with respect to atmospheric pressure when the blood circuit is filled with saline or blood, and the pumps are stopped. The offsets are measures of the static pressure generated by the fluid column in each section, e.g., withdrawal, return line and filtrate tube, of the circuit. Absent these offsets, a false disconnect or occlusion alarm could be issued by the monitor CPU (605 in
b illustrates the operation a similar fluid path as that shown in
Optical sensors which use infra red light of two or more wavelengths either transmissively or reflectively are also well suited for this application. Many of the issues with implanting such devices are now overcome, such as sensor size, variations in tissue and individual calibrations for each patient.
The solenoid controlled valve system shown in
a shows the plan view of a standard three port, two-way stopcock (e.g. Qosina P/N 99743). The stopcock has three ports and can connect two ports together at a time. The lever arm of the stopcock is represented by 410 with arms 403 and 404. The arms point to the ports that are connected 401 and 402. The port 405 is closed in this configuration.
b shows a cross-section of the same valve in the same lever position showing the ports 401 and 402 connected via the conduit 406. The conduit allows fluid to flow from port 401 to 402.
c shows the lever arm 410 rotated 90 degrees anti-clockwise from that displayed in
d shows a cross-section of the valve in the configuration of
a, 105b and 105c show a plan and elevation view of a rotary solenoid valve 500 for rotating the stopcock lever arm 410 shown in
The one way valves 130 and 131 in
The glucose control systems may also be used solely for the purposes of real time monitoring of blood glucose levels. To select this option the active control of glucose may be disabled via the membrane panel 610 ceasing the infusion of insulin. During this mode the user interface via the LCD displays a message to the user that active control of glucose has ceased. In this mode the device can be used to aid the medical practitioner in determining when it is necessary to titrate insulin manually. The alarm limits can be set to highlight when adjustments to manual titration of insulin are necessary obviating the need for the medical practitioner to continuously or intermittently monitor the patient. The monitoring system will alarm if the patients glucose level exceeds preset set alarm limits.
Glucose control systems mimic the body's natural insulin response to blood glucose levels as closely as possible in implanted glucose control applications, because excursions in the body without regard for how much insulin is delivered can cause excessive weight gain, hypertension and atherosclerosis. The proposed system suffers from very little signal time delay and lag. It is not necessary to wait for the insulin to transport through the interstitial space to the blood volume and back again to interstitial space to reach equilibrium. Insulin is infused directly into the blood and is transported directly to the interstitial space and organs. Control is based upon the measurement of the blood glucose level and the only delays and lag which occur are those of the insulin mixing in the blood volume, the transport of blood from the body to the filter and the transport of the ultrafiltrate to the sensor.
The withdrawal pressure controller is based upon the withdrawal blood flow but the infusion pressure controller is based upon both the blood flow and the insulin infusion. As the blood flow reduces in response to a partial occlusion the ultrafiltrate rate is reduce not to exceed 20% of the blood flow rate. When the blood flow rate is less than 10 ml/min, 25% of the target blood flow rate of for example 40 ml/min ultrafiltration is stopped and the device alarms to inform the user of the condition. If the set blood flow rate was 5 ml/min then ultrafiltration would be stopped when the blood flow dropped below 1.25 mL/min. Glucose infusion rates are well less than 1 ml/min and in reality have little or no affect on the pressure control. During a total occlusion when the system reverses glucose control is terminated for the duration of the reversal.
The rapid response of the control algorithm is illustrated by immediate adjustment of flow in response to pressure change in the circuit. This response is possible due to: (a) servo controlled blood pump equipped with a sophisticated local DSP (digital signal processing) controller with high bandwidth, and (b) extremely low compliance of the blood path.
Detection of bubbles during hemodvnamic monitoring Example embodiments of the present invention provide methods and apparatuses that enable the detection of bubbles so that hemodynamic performance can be assured following an automated blood analyte measurement. An example apparatus according to the present invention comprises a blood access system, adapted to remove blood from a body and infuse at least a portion of the blood back into the body. The infusion of at least a portion of the blood back in to the body can be done in a manner to assure that no bubbles of clinical significance are injected into the patient. Additionally an example embodiment can assess for the presence of bubbles in the fluid column that can affect hemodynamic monitoring performance. If a condition exists where hemodynamic monitoring performance cannot be assured, an example embodiment can provide appropriate warning or corrective actions.
An example method according to the present invention can comprise a bubble detection system used in conjunction with an automated analyte measurement and a hemodynamic monitoring system. The description herein will refer to an example blood access system for convenience. Other blood access systems and other analyte measurement techniques are also suitable for use with the present invention, as examples including those described in the patents and patent applications incorporated by reference herein.
Some example embodiments of the present invention provide for the detection of bubbles that would adversely impact the performance of the hemodynamic monitoring system. Some example embodiments of the present invention provide for both the detection of bubbles that can adversely impact the performance of the hemodynamic monitoring system and provide for a mechanism to remove these bubbles. Some example embodiments of the present invention can minimize the formation of bubbles during the automated blood measurement process.
An ICU (intensive care unit) pressure monitoring application is illustrated in
As shown in
A comparison between the pre-measurement waveform and post measurement waveforms can enable the detection of a bubble or bubbles that can affect hemodynamic performance. This comparison can take many forms to include simple subtraction, division, Fourier transform analysis, wavelet analysis, vector comparison, derivative processing, or any other mathematical treatment that enables a comparison between the two waveforms whereby the presence of a bubble can be detected.
For illustrative purposes
In implementation, the blood access system and the pressure measurement system must be able to exchange information. In general terms the integrated system is composed of four basic parts: (1) Blood movement system (2) pressure measurement system, (3) waveform analysis system and (4) display system. The various systems must be able to exchange information for the effective implementation of the bubble detection methodology. As shown in
An apparatus for the measurement of an analyte Embodiments of the present invention can facilitate accurate measurement of blood glucose by the clinician in a sterile manner. Embodiments of the present invention can also enable the calibration of the sensor at one or more calibration points. One desired analyte of measurement is glucose for the effective implementation of glycemic control protocols. Embodiments of the present invention can also be used for the measurement of other analytes such as arterial blood gases, lactate, hemoglobin, potassium and urea. Additionally, embodiments of the present invention can function effectively on a variety of blood access points and specifically enables hemodynamic monitoring. The present invention does not consume a significant amount of blood. Some embodiments of the present invention can re-infuse the blood into the patient, which can facilitate operation of the system in a sterile manner. A blood access system suitable for the applications mentioned above can have any one or combination of several desirable characteristics, described below.
A system according to the present invention can measure the blood by an electrochemical sensor. Such a measurement method need not consume any blood. Embodiments of the present invention provide for movement of blood into and out of the system in a manner that does not damage or activate the blood removed from the patient. One example embodiment uses a syringe although other pressure generating mechanisms can be utilized, including peristaltic pumps.
The blood access system can use fluid sources such as saline as a mechanism for cleaning the system of blood and for pushing the blood back into the patient.
Some example embodiments provide for minimization of mixing use low turbulent draw methods and tubing with low shear forces at the walls. Other considerations include the number of discontinuities included in the system, the number of luer connections and any discontinuity where cells can become trapped via stagnation. In some embodiments, the saline used for the final washing and subsequent cleaning of the circuit can be pumped to waste. The use of a waste or cleaning loop can provide multiple avenues for decreasing the saline infused into the patient.
The blood analyte measurement system must be able to manage or compensate for different vascular pressures. Some embodiments of the present invention enable blood pressure monitoring.
Some embodiments of the present invention enable standard pressure monitoring to occur between measurements. The pressure monitoring device can be located on a fluid pathway that is in fluid communication with the subject. In most embodiments, the pressure transducer is located close to the flow generation device but such a restriction in placement is not required. In fact the pressure monitoring device can be located on any fluid pathway that allows for accurate pressure measurements including waste pathways, calibration pathways, etc.
In some applications, it can be desirable for the blood access system to provide the ability to introduce and subsequently measurement a validation or calibration sample. Such a sample can be placed in the access system or provided in a manner that mimics a sample in the access system. Some embodiments of the present invention provide for a solution to be injected into the blood access system, or injected directly into the sensor.
Another embodiment uses an electronic check-sample to introduce a characteristic voltage or current signal into the instrumentation that verifies the performance of subsequent electronic and computational stages. One embodiment can mimic the detector signal with repeatable voltage waveforms produced by a digital-to-analog converter. These waveforms can mimic known amounts of the glucose signal to verify calibration accuracy.
In practice the vascular point can be kept open by the infusion of about 3 ml/hr of intravenous solution. Some embodiments of the present invention provide a capability to infuse solution at a similar rate to maintain movement of blood or saline across the catheter for the minimization of clot formation. This fluid infusion can be accomplished by gravity flow, a pressurized bag or other means.
It can be desirable for a system to have a cleaning capability, or example to reduce general contamination of the blood tubing and measurement system, the formation of small clots, or for general maintenance of the system. A solution used for cleaning the system can be infused into the patient or can be emptied into a waste bag. A solution used to push blood back into the patient can also accomplish cleaning of the system. Blood can often be a difficult substance to clean from a fluid management system. Accordingly, a cleaning cycle can utilize variable rates of flow, changes in direction of flow, and vibrate modes. A vibrate mode can take many forms; for example, the operator could push on the syringe then stop and push again. Such a push-stop-push technique is commonly used to clean peripherally inserted central catheters.
In some applications, it can be desirable to clean portions of the system with an enhanced cleaner such as one containing a detergent, surfactant, emulsifier, soap or the like. The enhanced cleaner can be used throughout the measurement cycle or introduced into the circuit during the end of an infusion cycle. In some use cases, the infusion cycle can be stopped before a significant portion (e.g., any, or any amount over some threshold) of the enhanced cleaner reaches the patient. A subsequent recirculation or cleaning cycle can cause the enhanced cleaner to flow through the system (but not enter the patient). A non-enhanced cleaner (e.g., saline) can be introduced into the circuit following the enhanced cleaner, such that the enhanced cleaner flows through the system, followed by the non-enhanced cleaner. The volumes of non-enhanced cleaner and enhanced cleaner can be controlled such that enhanced cleaner is not left in a portion of the system where it can be infused into the patient. In some applications, the useful life of the system can be extended by periodic cleaning with an cleaning agent.
The blood access system can contain a method for determining when the system becomes disconnected from the patient. For example, pressure detection, air detection, or the use of sound waves can be used to indicate that the system is not attached to a patient.
The blood access system can detect and prevent the infusion of air bubbles into the vascular system in any of several ways. Air bubbles can be removed prior to infusion into the patient can be by bubble traps or other filter mechanisms. Alternatively, the bubble can be routed to a waste line to clear it from the infusion circuit. In such a waste line embodiment, the system can continue operation without a requirement of pump stoppage.
The detection of vascular occlusion on either a withdrawal or an infusion can be important for patient safety. Some embodiments of the present invention can determine an occlusion by pressure monitoring or by examination of the sensor response. If fluid flow is unexpectedly stopped or slowed, the sensor response can change for multiple reasons such as heating.
A blood access system according to the present invention can be more effectively used for blood gas measurement by providing a means for compensation for such effects. Mechanisms for providing an accurate blood gas measurement can include the use of very short tubing lengths, allowing for equilibration of the blood with the tubing, minimizing the amount of out gassing by the tubing, compensation algorithms to account for changes, or a combination thereof. In the case of a loop system embodiment, the tubing can become equilibrated with the blood. In a second example embodiment, the amount of blood withdrawn can be large enough that the sample measured at the end of the draw has undergone minimal change. Another example embodiment measures the blood gases over the entire sample draw with a projection to an equilibrated point. Different blood draw mechanisms or operating parameters can be used for glucose measurements than are used for blood gas measurements. For example, equilibration concerns can indicate that a larger volume of blood be drawn for blood gas measurements than is required for glucose measurements.
In some applications of the present invention, it can be important to minimize the total amount of blood removed from the body and present in the circuit. For example, the clotting system can become activated when placed in contact with foreign materials. In such applications, a sample can be isolated at a location close to the patient. Any blood beyond that required for the sample can be quickly re-infused to minimize blood residence time. This isolated sample can then be measured without requiring a larger volume of blood to be present in the blood measurement system.
In some applications, the volume of venous blood accessible by the system can be supplemented by use of a standard pressure cuff proximal to the sampling site (e.g., for sampling through access at the lower arm, the cuff might be best positioned at the upper arm). The pressure cuff can be inflated at a preset time period before commencing blood withdrawal, forcing the venous pressure to the cuff pressure, increasing vascular volume, and increasing the available blood flow. As an example, the cuff can be inflated to 40 mmHg or a pressure less than arterial pressure if desired. The cuff can be deflated before commencing infusion, minimizing the back pressure experienced by the system during infusion. A pressure sensor within the circuit can be used as a trigger for the initiating the withdrawal of blood.
As some ICU patients have automatic blood pressure cuffs in place, the system can leverage the increased venous pressure and volume that occurs during the measurement process for the procurement of a blood sample. The operator or the system itself could sense the initiation of an automatic blood pressure measurement by changes in pressure, activation sounds or signals directly from the physiological monitor. For example the GE Dash™ 3000 Patient monitor has an analog blood pressure output that could be utilized for to trigger blood procurement. The blood access system would then utilize the increased venous pressure and associated blood volume due to cuff pressure and procure a blood sample. Such supplementation of the venous blood volume available can help facilitate the procurement of blood samples on a repeatable basis.
The present invention enables a multitude of options in both calibration and validation to ensure effective operation of the system. A basis for calibration is the use of fluid sources that can be used for calibration. These fluid sources can contain known analyte concentrations and can also contain additional additives that improve the overall performance of the system. Specific additives that can be contained in the fluids include additives that reduce bubble formation, facilitate cleaning of the circuit, reduce protein buildup on the sensing element, reduce cellular aggregation or platelet adhesion to the circuit. As examples, heparin and citrate can be used as additives that reduce the possibility of cellular aggregation. As used in this application; fluid sources, saline fluids, calibration fluids, or maintenance fluids are not intended to be restricted to only normal saline but further include any fluid it that can be administered to patients in environments such as the intensive care unit. Such fluids include but are not limited to normal saline, ¼ normal saline, ¼ normal saline, parenteral nutrition, and lactated ringers. Additionally, the fluid source can contain drugs or medications.
An important advantage of some embodiments of a blood analyte measurement system according to the present invention is the ability to perform sensor recalibration in a completely sterile manner. Infection risks within intensive care unit patients are extremely high. Some embodiments of the present invention can provide a calibration procedure that does not require “opening” of the system to potential bacteria.
The following figures illustrate a number of example embodiments of the present invention. Each example embodiment generally provides one or more of the desired attributes of the blood analyte measurement system as described above. For purposes of this disclosure, a fluid selection device will encompass any device that allows the user to select a designated fluid source or to stop fluid flow. Such a device can also have the ability to control flow rate from a fluid source. Some fluid selection devices enable selection of a fluid path that enables the removal or addition of fluid, for example by a syringe. A variety of flow selection devices can be used with the preferred embodiments, including but not limited to stop cocks (two way, three way, four way, etc.), pinch valves, butterfly valves, ball valves, rotating pinch valves and linear pinch valves, cams and the like. In some embodiments, a flow selection device selects the fluid source to be used and controls the flow rate from the fluid source.
As used in the disclosure a flow generation device controls the flow of fluids within the system by creating pressure gradients or allowing existing gradients to be transmitted such that fluid flow occurs. In some example embodiments, a flow generation device is configured to regulate the exposure of the sensor to the fluid sources including calibration fluids and blood from the host. In some example embodiments, the flow generation device is depicted as a syringe, but can include valves, cams, pumps, and the like. In one example embodiment, the flow generation device is a peristaltic pump. Other suitable pumps include volumetric infusion pumps, peristaltic pumps, and piston pumps. Flow generation devices also include any mechanism that creates a needed pressure gradient for operation. Such a pressure gradient can be generated by varying the pressure at the fluid source by raising/lowering the fluid source. Additionally pressure gradients can be created by placement of pressure cuff around a fluid source (typically an IV bag) or through the use of any mechanism that creates a pressurized bag.
As used in the following embodiments, a fluid source is any source of fluid used in the operation of the blood analyte measurement system. These fluid sources can be used for calibration, cleaning, verification and maintenance of the system. The fluid sources can contain known analyte concentrations and can also contain additional additives that improve the overall performance of the system. Specific additives that can be contained in the maintenance fluid include additives that reduce bubble formation, facilitate cleaning of the circuit, reduce protein buildup on the sensing element, reduce cellular aggregation or platelet adhesion to the circuit. As examples, heparin and citrate are known anticoagulants that reduce cellular aggregation. As used in this description fluid sources can include saline fluids or maintenance fluids can include any fluid it that is commonly administered to patients in environments such as the intensive care unit. Such fluids can include but are not limited to normal saline, ½ normal saline, and lactated ringers. In general terms, the saline fluid is the fluid used to maintain the patency of the access site. The calibration fluid is typically considered as a secondary fluid designed specifically to facilitate calibration or the overall operation of the device. These general terms are not intended to be restrictive but to provide a better context for the following descriptions.
Some of the example embodiments use a reservoir for fluid storage. A reservoir as used in this description includes any device that allows for the storage of a variable volume of fluid. Examples include but are not limited to a bag, a flexible pillow, a syringe, a bellows device, a device that can be expanded through pressure, an expandable fluid column, etc.
As shown in some of the example embodiments the flow generation device and reservoir can be combined into a single system, referred to as the flow generation and reservoir system. An example of such a system is a syringe which has both flow generation and reservoir capabilities. A syringe or syringe pump is defined broadly as a simple piston pump consisting of a plunger that fits tightly in a tube or container. The plunger can be pulled and pushed along inside a cylindrical tube (the barrel) or container, allowing the syringe to take in and expel a liquid. Such syringe systems for procurement of blood are used in clinical practice. Known syringe systems include Deltran Plus Needleless Arterial Blood Sampling System, VAMP Venous Arterial blood Management Protection, Portex Line Draw Plus, Becton Dickinson Safedraw, Smiths Saf-T Closed Blood Collection System, and Hospira SafeSet Closed Blood Sampling system (the foregoing are claimed as trademarks by their respective owners). Another example is a standard peristaltic pump coupled with a reservoir to provide both flow generation and reservoir capabilities.
As shown in some example embodiments, there is a waste channel such as a fluid pathway to a waste bag. During the blood withdrawal process, the fluid volume withdrawn can be transferred into a reservoir, returned to one of the fluid sources, or transferred to waste. For infection control purposes and to minimize contamination, it is typically undesirable to return the fluid volume to any of the fluid sources. Such a process can dilute a calibration at a fixed analyte concentration or add glucose or other analytes to a solution containing no analytes. Additionally, the potential introduction of red blood cells or other cellular matter results in contamination of the fluid source. If no reservoir is used and the fluid is not returned to a fluid source, then the fluid displaced by the withdrawal process can be transferred to a waste channel. One way valves can be used to ensure one way flow into the waste bag and out of the fluid source(s). Such unidirectional flows ensure that contamination does not occur
Push-pull system using syringe and peristaltic pump.
Blood Sample and Measurement Process:
1. The syringe is used to initiate the draw by moving the plunger away from the home position. The draw continues until an undiluted sample is present at the measurement sensor.
2. The blood interacts with measurement sensor and an analyte measurement is made.
3. Following completion of the measurement, the syringe is pushed towards the home position so that the blood is returned to the patient.
4. Following the return of the syringe to the home position, the pump is activated so as to move saline or calibration fluid through the system to the patient. This process helps clean the circuit and remove any remaining blood in the circuit.
5. Following cleaning of the circuit, the blood pump may remain active to maintain a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
The example embodiment of
1. Analyte measurements can be made on a very frequent basis.
2. The system operates with no blood loss.
3. The system operates with very little saline infusion and only during cleaning.
4. The system can work on multiple access locations, including arterial.
5. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access system.
6. The system can compensate for different size catheters through the volume pulled via the syringe.
7. The system provides for a one point calibration via the saline or calibration bag.
8. The system provides for access to the blood sample via a port in the circuit.
Push Pull System Based upon Syringe and Peristaltic Pump with Two Point Calibration.
Blood Sample and Measurement Process:
1. The syringe initiates the draw by moving the plunger away from the home position. The draw continues until an undiluted sample is present at the measurement sensor.
2. The blood interacts with measurement sensor and an analyte measurement is made.
3. Following completion of the measurement, the syringe is pushed towards the home position so that the blood is returned to the patient.
4. Following the return of the syringe to the home position, the pump is activated so as to move saline or calibration fluid through the system to the patient. This process helps clean the circuit and removed any remaining blood in the circuit.
5. Following cleaning of the circuit, blood pump may remain active to maintain a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
Calibration process. The system has two fluid sources that can be used to facilitate calibration of the sensor. The fluid sources have different glucose levels. The fluid selection device can be used to select the fluid of choice. The peristaltic pump can then move the fluid so that the sensor is exposed to the designated calibration fluid. The pump may remain active during this period and flow calibration fluid over the sensor pump may stop and allow the calibration fluid to simply remain in contact with the sensor.
The example embodiment of
1. The system can provide a two point calibration of sensor.
2. Analyte measurements can be made on a very frequent basis.
3. The system operates with no blood loss.
4. The system requires very little saline infusion and only during cleaning.
5. The system can work on multiple access locations including but not limited to arterial.
6. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access system.
7. The system can compensate for different size catheters through the volume pulled via the syringe.
8. The system provides for a one point calibration via the saline or calibration bag.
9. The system provides for access to the blood sample via a port in the circuit.
Push-Pull System Based upon Tubing Reservoir and Peristaltic Pump.
Blood Sample and Measurement Process:
1. Peristaltic pump initiates the draw by moving blood toward the sensor. The draw continues until an undiluted sample is present at the measurement sensor.
2. The blood interacts with measurement sensor and an analyte measurement is made.
3. Following completion of the measurement, the peristaltic pump infused the blood back into the patient.
4. Following the return of the blood to the patient, the pump is activated so as to move saline or calibration fluid through the system to the patient for additional cleaning. This process helps clean the circuit and removed any remaining blood in the circuit.
5. Following cleaning of the circuit, blood pump may remain active to maintain a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
The example embodiment of
1. The system is fully automatic system and does not require nurse intervention.
2. Analyte measurements can be made on a very frequent basis.
3. The system operates with no blood loss.
4. The system requires very little saline infusion and only during cleaning.
5. The system can work on multiple access locations including arterial.
6. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements after compensation for the pull and push of the blood access system.
7. The system can compensate for different size catheters through the volume pulled via the syringe.
8. The system provides for a one point calibration via the saline or calibration bag.
9. The system provides for access to the blood sample via a port in the circuit.
Push Pull System Based upon Syringe.
Blood Sample and Measurement Process:
1. The system is calibrated as described below. Following calibration the operator initiates a blood draw by moving the syringe plunger away from the home position. The draw continues until an undiluted sample is present at the measurement sensor. The determination of an undiluted sample can be by volume drawn, visual inspection or the sensor sample state methods described above.
2. The blood interacts with measurement sensor and an analyte measurement is made. The blood can be flowing or not flowing across the sensor during the measurement.
3. Following completion of the measurement, the syringe is pushed towards the home position so that the blood is returned to the patient. At this juncture the majority of all blood has been returned to the patient.
4. If additional cleaning of the circuit is desired, fluid from either fluid source can be used to clean the circuit further. The fluid can simply be flowed through the system or drawn into the syringe. If drawn into the syringe, the operator can use a push-stop-push flow pattern to facilitate cleaning. The cleaning process helps to maintain the circuit for future use and prevent clotting of the circuit.
5. Following cleaning of the circuit, fluid for may continue to flow toward the patient to create a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
Calibration process. The system has two fluid sources that can be used to facilitate calibration of the sensor. The fluid sources have different analyte levels. The fluid selection device can be used to select one of the two fluids. Gravity feed or pressure moves the fluid so that the sensor is exposed to the designated calibration fluid. During the calibration process, calibration fluid can be flowed over the sensor or fluid may simply remain in contact with the sensor. As described elsewhere in this specification it can be advantageous to maintain the sensor in a low analyte containing solution prior to measurement.
The example embodiment of
1. Analyte measurements can be made on a very frequent basis.
2. The system operates with no blood loss.
3. The system can work on multiple access locations including arterial.
4. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements.
5. The system can compensate for different size catheters through the volume pulled via the syringe.
6. The system provides for a two point calibration via the two fluid sources.
7. The system provides for access to the blood sample via a port or stopcock in the circuit.
8. Additional samples can be inserted into the system via the access port.
9. The system provides completely sterile operation.
Push Pull system based upon Syringe with Sensor Near Patient.
For calibration, the system can use two fluid sources with different glucose concentrations. The fluid selection device can be used to select the fluid of choice, or a controlled combination of fluids. Gravity feed or pressure moves the fluid so that the sensor is exposed to the designated calibration fluid. During the calibration process, calibration fluid can be flowed over the sensor or calibration fluid can simply remain in contact with the sensor. Following calibration the sensor can be exposed to a low glucose containing solution prior to measurement.
Push Pull system based upon Syringe with Calibration Fluid Pathway.
Blood Sample and Measurement Process.
1. The system is calibrated as described below. Following calibration the operator initiates a blood draw by moving the syringe plunger away from the home position. The draw continues until an undiluted sample is present at the measurement sensor. The determination of an undiluted sample can be by volume drawn, visual inspection or the sensor sample state methods described above.
2. The blood interacts with measurement sensor and an analyte measurement is made. The blood may be flowing or not flowing across the sensor during the measurement.
3. Following completion of the measurement, the syringe is pushed towards the home position so that the blood is returned to the patient. At this juncture the majority of all blood has been returned to the patient.
4. If additional cleaning of the circuit is desired, fluid from either fluid source can be used to clean the circuit further. The fluid can simple by flowed through the system or drawn into the syringe. If drawn into the syringe, the operator can use a push-stop-push flow pattern to facilitate cleaning. The cleaning process helps to maintain the circuit for future use and prevent clotting of the circuit.
5. Following cleaning of the circuit, fluid can continue to flow toward the patient to create a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
Calibration Process. The system has two fluid sources that can be used to facilitate calibration of the sensor. The fluid sources have different analyte levels. The fluid selection device can be used to select the fluid of choice. Several different methods can be used to move the fluid over the sensor. As an example, gravity feed can move the fluid so that the sensor is exposed to the designated calibration fluid. As another example, the fluid sources can be pressurized to move the fluid. As another example, additional flow generation devices can be added to create flow. As shown in
The example embodiment of
1. Analyte measurements can be made on a very frequent basis.
2. The system operates with no blood loss.
3. The system can work on multiple access locations including arterial.
4. The system can contain a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements.
5. The system can compensate for different size catheters through the volume pulled via the syringe.
6. The system provides for a two point calibration via the two fluid sources.
7. The system provides for access to the blood sample via a port or stopcock in the circuit.
8. Additional samples can be inserted into the system via the access port (not shown).
9. The system provides completely sterile operation.
10. The use of the calibration bypass circuit helps to limit the amount of calibration solution infused into the patient.
Push Pull system based upon Syringe with Waste Fluid Pathway.
Blood Sample and Measurement Process.
1. The system is calibrated as described below. Following calibration the operator initiates a blood draw by moving the syringe plunger away from the home position. The draw continues until an undiluted sample is present at the measurement sensor. The determination of an undiluted sample can be by volume drawn, visual inspection or the sensor sample state methods described above.
2. The blood interacts with measurement sensor and an analyte measurement is made. The blood may be stagnant during the measurement process or flowing across the sensor.
3. Following completion of the measurement, the syringe is pushed towards the home position so that the blood is returned to the patient At this juncture the majority of all blood has been returned to the patient. At any point during the infusion process, the operator may elect to direct the fluid to waste.
4. If additional cleaning of the circuit is desired, fluid from either fluid source can be used to clean the circuit further. The fluid used for cleaning can be directed to waste by fluid selection device #2. The fluid can flow through the system or be drawn into the syringe. If drawn into the syringe, the operator can use a push-stop-push flow pattern to facilitate cleaning. The cleaning process helps to maintain the circuit for future use and prevent clotting of the circuit.
5. Following cleaning of the circuit, fluid can continue to flow toward the patient to create a “keep vein open” fluid infusion towards the patient.
6. The measurement results and any historical information are communicated to a user, e.g., shown on a display (not shown).
Calibration Process. The system has two fluid sources that can be used to facilitate calibration of the sensor. The fluid sources have different glucose levels. The fluid selection device can be used to select the fluid of choice. Gravity feed moves the fluid so that the sensor is exposed to the designated calibration fluid or alternatively, the fluid sources can be pressurized to move the fluid. The calibration solution is delivered to the sensor and either be infused into the patient or directed to the waste bag. During the calibration process, calibration fluid may be flowed over the sensor or fluid may simply remain in contact with the sensor. Following calibration of the sensor with the calibration fluid, the fluid selection device #1 is configured to select the saline fluid. As described elsewhere in this specification it can be advantageous to maintain the sensor in a low analyte containing solution prior to measurement. Based upon these advantages and the general desire not to infuse the patient with high analyte concentration fluid, the higher analyte containing solution would be the calibration solution. The saline solution can be simply saline, other IV fluids, an IV fluid with anticoagulant, or a calibration solution with a lower analyte value.
The example embodiment of
1. Analyte measurements can be made on a very frequent basis.
2. The system operates with no blood loss.
3. The system can work on multiple access locations including arterial.
4. The system can contain a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements.
5. The system can compensate for different size catheters through the volume pulled via the syringe.
6. The system provides for a two point calibration via the two fluid sources.
7. The system provides for access to the blood sample via a port or stopcock in the circuit.
8. Additional samples can be inserted into the system via the access port (not shown).
9. The system provides completely sterile operation.
10. The use of the waste bypass pathway helps to limit the amount of solution infused into the patient.
Push Pull system based upon Syringe with Calibration and Waste Fluid Bypass Circuits.
Push Pull System Based upon Syringe with Sensor Access.
Two Syringe Push Pull System.
Two Reservoir Push Pull System with Peristaltic Pump.
Push Pull System based upon Peristaltic Pump.
Push Pull System Based upon Syringe with Flow Divider Bypass.
Push Pull System Based upon Syringe with Flow Divider Bypass.
The example embodiment of
1. Analyte measurements can be made on a very frequent basis.
2. The system operates with no blood loss.
3. The system can work on multiple access locations including arterial.
4. The system contains a pressure monitor that can provide arterial, central venous, or pulmonary artery catheter pressure measurements.
5. The system can compensate for different size catheters through the volume pulled via the syringe.
6. The system provides for a two point calibration via the two fluid sources.
7. The system provides for access to the blood sample via a port or stopcock in the circuit.
8. Additional samples can be inserted into the system via the access port (not shown).
9. The system provides completely sterile operation.
10. If the sensor has a small cross sectional area or significant compliance, then the bypass circuit enables pressure monitoring without corruption of the signal during non-measurement periods.
11. If the sensor has a small cross sectional area or can be damaged by flow, then the bypass circuit can be used. In practice, an undiluted sample could be drawn to the sensor location via the bypass loop. At this point in the measurement cycle, the fluid selection devices changes to flow through the sensor occurs. The additional blood needed to fill the sensor is small in comparison the amount needed to get an undiluted sample to the sensor.
System configuration.
System configuration.
Calibration and Maintenance. The present invention can also provide improved methods for maintaining and calibrating an analyte sensor such as a glucose sensor for improved performance and safety. Via recognition of enzyme kinetics, the improved methods facilitate a faster measurement response which limits the potential for blood coagulation. The improved methods also reduce enzyme suppression which can lead to inaccurate results. The improved methods, via the use of a low glucose concentration maintenance fluid, create a safer system by limiting the potential for erroneously high readings.
Method for determining the quality of a biological sample procured for ex vivo analysis The example blood access system is shown in
The console can be attached to the patient through a sterile disposable sensor set designed for use with the console. As an example, the sensor set can be intended for use on a single patient for up to 72 hours. The sensor set, which can be attached to the patient using a dedicated peripheral venous catheter or other access location, provides convenient vascular access that enables automated withdrawal of a whole blood sample into an in-line optical cuvette for glucose measurement by means of optical transmission spectroscopy. When a glucose measurement is made, the system withdraws blood into the sensor set under controlled flow and pressure conditions. The system maintains flow of the blood during the glucose measurement, and reinfuses at least a portion of the blood to the patient once the glucose measurement is complete. The sensor set is connected to a saline bag which provides a flushing solution that keeps the lines and catheter free of thrombus formation and blood accumulation. In addition, the sensor set has a second path that connects to a waste bag through a T-junction near the patient connection. This path to waste enables thorough flushing and cleaning of the system between measurement cycles without infusing excess fluid to the patient.
The Console comprises:
Pumps—Pumps provide the ability to move blood and saline between the patient and the optical cuvette. There are two peristaltic pumps, the blood pump and the flush pump, that execute a programmed flow control sequence for the procurement of a blood sample for measurement, reinfusion of the blood following measurement and thorough cleaning of the sensor set after reinfusion. The sampling sequence is initiated by a manual request or pre-programmed, for example at a frequency or interval specified by the user.
Control System—Electronic controls and software manage pump speeds and directions and monitor the sensor set pressures during the blood measurement cycle. The blood measurement cycle will 1) maintain patency between blood samples, 2) withdraw a blood sample, 3) return the blood sample, and 4) clean the sensor set. If the Control System detects fault events in the blood access cycle, the control system will either execute automated procedures to clear the faults, or it will alert the user when faults cannot be automatically cleared. The Console also contains the optical measurement system, consisting of a light source and spectrometer for making the NIR glucose measurement. Glucose measurement algorithms can be resident in system nonvolatile memory.
Touch Screen—The Console can incorporate a touch screen computer for entering patient information and setting device operation parameters. The Console also provides visual display of measured glucose values as well as information associated with system operation including visual and audible alerts and alarms.
The Sensor Set includes:
Circuit Tubing—There are two tubes extending to the patient from the Cassette. One tube is used to convey blood and saline between the patient and optical cuvette. A second tube to the patient aids catheter flushing and returns saline used to clean the optical cuvette to the sensor set waste bag. Within the Cassette are a number of one-way valves used to isolate returned waste fluid from the patient.
Extension Set—The extension set connects the patient catheter to the disposable sensor set. The extension set includes a stopcock for lab blood draws and catheter maintenance, provides strain relief for ease of use and patient safety, and facilitates the attachment of the automated glucose measurement system to the patient.
Pump Cassette—The cassette attaches directly to the console and includes all electrical connections, peristaltic pump loops and one-way valves needed for operation. The cassette components comprise:
Pressure Sensors—Measure pressures inside the sensor set in the proximity of the pump tubing. There are two pressure sensors: the blood line pressure sensor and the flush line pressure sensor. Each sensor measures pressures on the patient side of the pump.
Tubing Reservoir—As a blood sample is withdrawn from the patient to the cuvette the first portion of the sample is diluted with saline. The diluted blood is pumped past the cuvette into the Tubing Reservoir. This overdraw enables measurement of an undiluted blood sample in the optical cuvette. The Tubing Reservoir is comprised of a vertical coil of tubing.
Bubble detector—The Blood Access System has a bubble detector that detects the presence of bubbles in the sensor set near the Extension Set. The bubble detector is used to ensure patient safety and to improve overall system functionality.
Cuvette—a glass tube with rectangular cross-section and fixed path length in which the blood measurement is made. The cuvette provides the interface between the sensor set and the spectrometer in the Optical Measurement System.
Two Fluid Bags can be useful for system operation:
Saline bag (user-supplied)—The Blood Access System pumps are able to move blood by pumping a column of sterile saline in advance of the blood sample. The sensor set accordingly requires a connection to a sterile saline bag. The sensor set is designed so that either the blood or flush pumps can pump fluid from the saline bag. One way valves ensure fluids cannot be pumped into the saline bag.
Waste bag—The Blood Access System requires a waste bag for collection and disposal of waste fluid generated during the flush and cleaning cycles. The sensor set is designed so that either the blood pump or flush pump can pump fluid into the waste bag. One way valves ensure fluids cannot be pumped out of the waste bag.
Operation of an Example Embodiment From an operational standpoint, the instrument can be separated into two primary functional subsystems that work in tandem to achieve the automated glucose measurement: 1) Blood Access System and 2) Optical Measurement System. The role of the Blood Access System is to safely and reliably draw a homogeneous blood sample from the patient into the optical cuvette, maintain the sample in a stable condition during the course of the optical measurement, return the blood to the patient and then flush and prepare the system for the next measurement cycle. The role of the optical measurement system is to collect NIR transmission spectra from the blood contained within the sensor set cuvette and to apply the appropriate signal conditioning and spectral data processing to confirm that an undiluted sample is present in the cuvette and to make a glucose determination from that sample.
The Blood Access System (see
Procurement of an undiluted blood sample for optical measurement;
Minimization of blood loss and fluids infusion;
Continued patency of the catheter, tubing and optical cuvette.
Procurement of an undiluted blood sample for optical measurement. The automated blood access system can use a sensor set that is primed with saline for safe and effective blood flow control. As the blood is drawn from the patient through the tubing, the blood/saline interface exhibits a parabolic flow profile and is characterized by a broadened transition zone of blood mixed with saline. The transition zone between undiluted blood and saline increases as the draw continues. Since the glucose measurement system can be sensitive to dilution effects, diluted blood is drawn past the glucose sensor and collected in the tubing reservoir until an undiluted sample is present in the cuvette. The present invention can be used to determine when an appropriate sample is present in the optical cuvette. Upon arrival of an appropriate sample, the system can initiate the measurement process. In the example embodiment, the measurement system is an optical measurement system but other measurement methods can be used. Other suitable methods can include indwelling electrochemical sensors, enzymatic sensors, sensors that work when in contact with blood such as those made by Dexcom and Abbott, standard sensors that work on a sample of blood and other optical sensing methods that use serum, plasma, supernatants or ultrafiltrates.
Minimization of blood loss and fluids infusion. Because of the blood-saline mixing at the interface between the two fluids, reinfusion of blood can involve some saline infusion to the patient. Similarly, when the system diverts fluid to waste during the cleaning process there can be an amount of residual blood in the tubing that goes to waste with the flush solution. There is a tradeoff between the amount of saline infused to the patient with each cycle versus the amount of blood diverted to waste. The automated Blood Access System can provide an optimized balance to minimize blood loss while simultaneously minimizing the saline infused to the patient with each sample. Typical standard maintenance intravenous fluid infusion rates are 125 mL/hr (3.0 liters per day) for a typical sized person. The procurement of automated measurements every 30 minutes would result in 48 paired measurements over the 24 hour period. If each measurement cycle infuses 9 ml of saline to the patient this will represent approximately 15% of a typical fluid maintenance rate. To minimize saline infusion during the measurement cycle and subsequent cleaning requires careful monitoring of infused volume to compensate for blood-saline mixing, and the use of specific fluid flow rates and patterns that optimize cleaning of the tubing during the blood infusion and cleaning. In regular operation, the only blood that is lost is that which is cleared from the walls of the tubing into the waste bag during the flush cycle. The amount of blood lost is less than 1004 per sample or approximately 5 mL/day at a 30 minute sample interval.
Patency of the catheter, tubing and cuvette. Stationary extracorporeal blood, unless treated with anticoagulants, tends to adhere to foreign surfaces and coagulates within a few minutes. To avoid these issues the process of blood withdrawal, measurement, reinfusion and cleaning can be completed effectively within a time frame that prevents blood coagulation and achieves effective cleaning of the circuit so aggregation of blood components within the walls of the tubing, cuvette and catheter of the sensor set does not occur.
The plumbing network (see
Exception Detection and Management. Exceptions to the normal operation of the automated glucose measurement system occur when occlusions and air bubbles appear during the operation of the Blood Access System. The Blood Access System detects and manages occlusions, restrictions and air bubbles that can occur during any phase of the operational cycle. The system utilizes different recovery methods depending upon the stage of operation. Using measurements from the two pressure transducers near the pumps, the system can identify the location of a problem and will automatically clear the problem or alert the user so that it can be cleared manually. If the exception requires the user to take an action this is called an intervention.
In the operation of a Blood Access System, interventions that can occur include:
Occlusions due to positional occlusions of the catheter;
Air bubbles (typically from saline out gassing) when the system cannot automatically flush them to waste.
The automated glucose measurement system can use the following information for occlusion detection and management:
Pressure thresholds based upon the stage of operation;
Relationship of pressure between the two pressure sensors;
The time history of the pressure relationships between the pressure sensors;
The time history of pressure measurements (trend changes);
Dissipation of pressure within the circuit (the pressure change between the withdrawal and sample stages);
Time to complete a stage or time to complete stages;
Pressure trends between subsequent withdrawals;
Estimated flow rates based on pump rotational speeds and differential pressure readings.
This information can be incorporated into a decision flow chart that determines if an occlusion has occurred and initiates an appropriate recovery process. Generally, the system determines the stage of operation, the presence of blood in the circuit, the location of the occlusion and implements a recovery process to the extent possible. Depending upon the recovery results, an operator such as a nurse can be alerted. For example if an occlusion occurs in withdrawal, the system automatically re-infuses any blood withdrawn and a small amount of additional saline. The system will re-attempt a second blood draw. If occlusion is detected a second time the system again re-infuses any blood removed and automatically returns to a safe condition and alerts the care provider to address the problem.
The example system can also detect air bubbles in the line and prevent them from being infused to the patient. Common causes of air bubbles include out-gassing of the saline as it is subjected to negative pressure, and an increase in ambient temperature compared to the storage temperature of the saline. The automated glucose measurement system detects air bubbles below the T-junction near the Extension Set and stops flow upon detection. The system then determines the stage of operation, and the presence of blood in the circuit. Based upon this information a bubble management protocol is initiated. In most cases the bubble is pulled from the air bubble detector and past the T-junction into the flush line. Once isolated in the flush line, the system can flush the bubble to the waste bag for disposal. The system then resumes normal operation and provides an alert to an operator such as a nurse.
The Blood Access System operation can be described as 6 primary stages:
Draw initialization and clearing the catheter access;
Blood withdrawal;
Optical measurement;
Infusion;
Cleaning (incorporating Scrub, Recirculation, and Catheter Flush sub-stages);
KVO (“keep vein open”).
Draw Initialization Stage; Clearing Catheter Access. Before the blood draw is started, both the blood and flush pumps are controlled to issue a pulse of saline to clean away any residual blood in the catheter tip. This prepares the catheter for the subsequent withdrawal of blood.
Blood Withdrawal Stage. The blood pump is used to withdraw the blood sample and position non-diluted blood in the cuvette. To minimize the total draw time, about 80% of the total required blood volume is first drawn at a rapid flow rate. A constant-pressure-based draw method is used to compensate for the varying mix of saline and blood, and to achieve maximum flow rate constrained by the constant upstream negative pressure that keeps fluid degassing minimized. As blood replaces saline in the blood line, viscosity and resistance to flow increase so that for a constant upstream pressure, flow rate decreases over time. The termination of this stage of the draw is determined by what is referred to as optical termination. Optical termination is the optical detection of when a sample appropriate for measurement has filled the cuvette. After the optical termination of the withdrawal stage, the measurement of the sample can be initiated. An example of a specific optical termination method will be disclosed in detail below. Non-optical methods of detecting the arrival of an undiluted blood sample, such as those described elsewhere herein, can also be used.
Optical Measurement Stage. Following the rapid draw, the pump flow rate is slowed to a constant flow rate of 0.5 mL/min to maintain suspension of the red blood cells in plasma during optical measurement. During the 60 second measurement period an additional 500 μL of blood is withdrawn.
Infusion Stage. After the measurement is completed, reinfusion immediately begins as a progression of stages that are designed to return the blood quickly to the patient and clean the tubing and optical cuvette. The initial stage of infusion uses a constant pressure-based control which results in a variable flow rate that minimizes the time to reinfuse the blood to the patient. This stage reinfuses nearly all of the blood that was withdrawn, leaving a remaining saline-blood mixture at the end of the blood line. The first stage of the reinfusion can be completed within three minutes of the initiation of blood withdrawal.
The 2nd stage of infusion involves a repetitive back and forth motion of the blood pump such that during half of one cycle the pump pushes blood forward at a constant flow rate, and during the second half of the cycle blood is pulled back at about half the rate. The asymmetric cycle helps wash away any cells or other blood products that could potentially adhere to the tubing walls. During this stage of infusion, flow is controlled to limit the pressure.
The 3rd stage of infusion begins with the blood pump executing a repetitive alternating forward-pause motion that provides pulsatile acceleration and washing of blood products from the tubing walls. The flow in this stage is also pressure controlled.
It is possible to use another optical termination type measurement to determine when the majority of blood has been re-infused back into the patient and exited the optical cell. The basic principles are the same but in this application the termination measurement is looking for stability in the saline sample instead of stability in the blood sample. The method can be used to make sure there is no residual blood in the cell.
Cleaning Stages. At this point in the cycle more than 97% of the blood has been returned to the patient; the next stages focus on a more thorough cleaning of the cuvette, tubing and catheter.
Scrub Stage. The first stage of cleaning is known as ‘scrub’. The scrub stage involves rapid, reverse-synchronized back and forth motion of the blood and flush pumps so that fluid movement occurs only within the blood and flush lines with minimum net fluid flow to or from the patient. The flow is not turbulent, but the rapid oscillations create accelerations that help to wash any small amount of residual blood that can collect on the walls of the tubing and cuvette.
Recirculation Stage. Once the remaining blood products have been lifted off the tubing and cuvette walls into the mainstream by the scrub stage, the blood and flush pumps are operated at a constant, nearly synchronized rate, flushing the lines into the waste bag while flushing a small amount of saline to the patient to keep blood from migrating back into the catheter.
It is also possible to use an optical termination type measurement to access when the cell has been adequately cleaned. Even small amounts of protein can be assessed optically. Thus, the optical measurement method can be used to determine when adequate cleaning of the cell has occurred. In use the method can compare the spectral response from a prior measurement to the current measurement. If there is optical evidence of additional protein in the cell then additional cleaning might be indicated.
Catheter Flush Stage. In the final cleaning stage high flow rate controlled volume pulses completely clear the catheter extension line, tubing connectors and the catheter itself.
KVO Stage. The period between measurement cycles is KVO (Keep Vein Open). KVO provides a low, constant flow rate into the patient to prevent blood from migrating into the catheter thus maintaining an open blood access connection between draws.
The Blood Access System operation comprises 6 primary stages:
Draw initialization and clearing the catheter access;
Blood withdrawal;
Optical measurement;
Infusion;
Cleaning (incorporating Scrub, Recirculation, and Catheter Flush sub-stages);
KVO (“keep vein open”).
Draw Initialization Stage; Clearing Catheter Access. Before the blood draw is started, both the blood and flush pumps are controlled to issue a pulse of saline to clean away any residual blood in the catheter tip. This prepares the catheter for the subsequent withdrawal of blood.
Blood Withdrawal Stage. The blood pump is used to withdraw the blood sample and position non-diluted blood in the cuvette. To minimize the total draw time, about 80% of the total required blood volume is first drawn at a rapid flow rate. A constant-pressure-based draw method is used to compensate for the varying mix of saline and blood, and to achieve maximum flow rate constrained by the constant upstream negative pressure that keeps fluid degassing minimized. As blood replaces saline in the blood line, viscosity and resistance to flow increase so that for a constant upstream pressure, flow rate decreases over time. The termination of this stage of the draw is determined by what is referred to as optical termination. Optical termination is the optical detection of when a sample appropriate for measurement has filled the cuvette. After the optical termination of the withdrawal stage, the measurement of the sample can be initiated. An example of a specific optical termination method will be disclosed in detail below. Non-optical methods of detecting the arrival of an undiluted blood sample, such as those described elsewhere herein, can also be used.
Optical Measurement Stage. Following the rapid draw, the pump flow rate is slowed to a constant flow rate of 0.5 mL/min to maintain suspension of the red blood cells in plasma during optical measurement. During the 60 second measurement period an additional 500 μL of blood is withdrawn.
Infusion Stage. After the measurement is completed, reinfusion immediately begins as a progression of stages that are designed to return the blood quickly to the patient and clean the tubing and optical cuvette. The initial stage of infusion uses a constant pressure-based control which results in a variable flow rate that minimizes the time to reinfuse the blood to the patient. This stage reinfuses nearly all of the blood that was withdrawn, leaving a remaining saline-blood mixture at the end of the blood line. The first stage of the reinfusion can be completed within three minutes of the initiation of blood withdrawal.
The 2nd stage of infusion involves a repetitive back and forth motion of the blood pump such that during half of one cycle the pump pushes blood forward at a constant flow rate, and during the second half of the cycle blood is pulled back at about half the rate. The asymmetric cycle helps wash away any cells or other blood products that could potentially adhere to the tubing walls. During this stage of infusion, flow is controlled to limit the pressure.
The 3rd stage of infusion begins with the blood pump executing a repetitive alternating forward-pause motion that provides pulsatile acceleration and washing of blood products from the tubing walls. The flow in this stage is also pressure controlled.
It is possible to use another optical termination type measurement to determine when the majority of blood has been re-infused back into the patient and exited the optical cell. The basic principles are the same but in this application the termination measurement is looking for stability in the saline sample instead of stability in the blood sample. The method can be used to make sure there is no residual blood in the cell.
Cleaning Stages. At this point in the cycle more than 97% of the blood has been returned to the patient; the next stages focus on a more thorough cleaning of the cuvette, tubing and catheter.
Scrub Stage. The first stage of cleaning is known as ‘scrub’. The scrub stage involves rapid, reverse-synchronized back and forth motion of the blood and flush pumps so that fluid movement occurs only within the blood and flush lines with minimum net fluid flow to or from the patient. The flow is not turbulent, but the rapid oscillations create accelerations that help to wash any small amount of residual blood that can collect on the walls of the tubing and cuvette.
Recirculation Stage. Once the remaining blood products have been lifted off the tubing and cuvette walls into the mainstream by the scrub stage, the blood and flush pumps are operated at a constant, nearly synchronized rate, flushing the lines into the waste bag while flushing a small amount of saline to the patient to keep blood from migrating back into the catheter. It is also possible to use an optical termination type measurement to access when the cell has been adequately cleaned. Even small amounts of protein can be assessed optically. Thus, the optical measurement method can be used to determine when adequate cleaning of the cell has occurred. In use the method can compare the spectral response from a prior measurement to the current measurement. If there is optical evidence of additional protein in the cell then additional cleaning might be indicated.
Catheter Flush Stage. In the final cleaning stage high flow rate controlled volume pulses completely clear the catheter extension line, tubing connectors and the catheter itself.
KVO Stage. The period between measurement cycles is KVO (Keep Vein Open). KVO provides a low, constant flow rate into the patient to prevent blood from migrating into the catheter thus maintaining an open blood access connection between draws.
In the “1st Background” phase, measurements can be taken of the fluid present at the measurement site, which fluid should be primarily saline (or other system fluid, and not blood). The measurements can be analyzed for variance and trends as described elsewhere herein. If the variance and trends do not match those expected for this phase of operation, then an error can be indicated.
In the “Blood draw” phase, measurements can be taken of the fluid that is present at the measurement site, which fluid should be transitioning from primarily saline (or other system fluid) to a mix of saline and blood to blood with minimal saline. The measurements can be analyzed for variance and trends as described elsewhere herein. As examples, any parameters that are present differently in blood than in saline (e.g., optical scatter, or some analyte concentrations) should show a time trend from the saline value to the blood value, then become stable after the measurement site is largely filled with blood. If the measurements do not indicate that the fluid is transitioning to substantially pure blood, then an error can be indicated.
In the “Sample” phase, the measurement site should be exposed to substantially pure blood sample. Measurements taken should show variance and stability consistent with such a sample, e.g., generally little or no trends, and variability within the range established by the measurement system itself. If the measurements are not consistent with a substantially pure blood sample, then an error can be indicated.
In the “Reinfuse”, “Flush”, and “KVO” phases, the measurement site should be exposed to varying combinations of blood and saline, ending with substantially pure saline by the KVO phase. Measurements taken during these phases should have trends and variability consistent with a declining proportion of blood present at the measurement site. If they do not, then an error can be indicated.
Having thus described in detail certain embodiments of the present invention, it is to be understood that the invention described herein is not to be limited to particular details set forth in the above description as many apparent variations and equivalents thereof are possible without departing from the spirit or scope of the present invention.
This application claims priority as a continuation in part of the following U.S. application Ser. Nos. 11/679,826, filed Feb. 27, 2007, 11/679,837, filed Feb. 28, 2007, 11/679,839, filed Feb. 28, 2007, 11/860,544, filed Sep. 25, 2007, 11/860,545, filed Sep. 25, 2007, 12/241,221, filed Sep. 30, 2008, 12/576,303, filed Oct. 9, 2009, 12/577,153, filed Oct. 10, 2009, 12/641,411, filed Dec. 18, 2009, 12/714,100, filed Feb. 26, 2010, 12/884,175, filed Sep. 16, 2010, 11/679,835 filed Feb. 27, 2007, which claimed priority to U.S. provisional 60/791,719 filed Apr. 12, 2006, 11/842,624, filed Aug. 21, 2007, 11/101,439, filed Apr. 8, 2005, 12/188,205, filed Aug. 8, 2008, 12/108,250, filed Apr. 23, 2008, 12/576,121, filed Oct. 8, 2009, 10/850,646, filed May 21, 2004; And claims priority to the following U.S. provisional applications: 60/791,719, filed Apr. 12, 2006, 60/737,254, filed Nov. 15, 2006, 61/105,600, filed Oct. 15, 2008, 61/104,252, filed Oct. 9, 2008, 61/104,193, filed Oct. 9, 2008, 60/955,636, filed Aug. 13, 2007, 60/913,582, filed Apr. 24, 2007, 60/991,373, filed Nov. 30, 2007, 61/044,004, filed Apr. 10, 2008, 60/976,775, filed Oct. 1, 2007, 61/444,118, filed Feb. 17, 2011; And as a continuation in part of the following PCT applications: PCT/US2006/060850, filed Nov. 13, 2006, PCT/US2009/037398, filed Mar. 17, 2009, PCT/US2009/037402, filed Mar. 17, 2009. Each of the foregoing applications is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60791719 | Apr 2006 | US | |
| 60737254 | Nov 2005 | US | |
| 60791719 | Apr 2006 | US | |
| 60791719 | Apr 2006 | US | |
| 60791719 | Apr 2006 | US | |
| 60955636 | Aug 2007 | US | |
| 60955636 | Aug 2007 | US | |
| 60976775 | Oct 2007 | US | |
| 61104193 | Oct 2008 | US | |
| 61104252 | Oct 2008 | US | |
| 61105600 | Oct 2008 | US | |
| 60791719 | Apr 2006 | US | |
| 60737254 | Nov 2005 | US | |
| 61444118 | Feb 2011 | US |
| Number | Date | Country | |
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| Parent | 11101439 | Apr 2005 | US |
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| Parent | 11679826 | Feb 2007 | US |
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| Parent | PCT/US2006/060850 | Nov 2006 | US |
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| Parent | 11679837 | Feb 2007 | US |
| Child | PCT/US2006/060850 | US | |
| Parent | PCT/US2006/060850 | Nov 2006 | US |
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| Parent | 11679839 | Feb 2007 | US |
| Child | PCT/US2006/060850 | US | |
| Parent | PCT/US2006/060850 | Nov 2006 | US |
| Child | 11679839 | US | |
| Parent | 11679835 | Feb 2007 | US |
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| Parent | 12188205 | Aug 2008 | US |
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| Parent | 11842624 | Aug 2007 | US |
| Child | 12188205 | US | |
| Parent | 11860544 | Sep 2007 | US |
| Child | 11842624 | US | |
| Parent | 11860545 | Sep 2007 | US |
| Child | 11860544 | US | |
| Parent | 12241221 | Sep 2008 | US |
| Child | 11860545 | US | |
| Parent | 12576121 | Oct 2009 | US |
| Child | 12241221 | US | |
| Parent | 12576303 | Oct 2009 | US |
| Child | 12576121 | US | |
| Parent | 12577153 | Oct 2009 | US |
| Child | 12576303 | US | |
| Parent | 12641411 | Dec 2009 | US |
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| Parent | 12714100 | Feb 2010 | US |
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| Parent | 12884175 | Sep 2010 | US |
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| Parent | PCT/US2009/037398 | Mar 2009 | US |
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| Parent | PCT/US2009/037402 | Mar 2009 | US |
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| Parent | 11679826 | Feb 2007 | US |
| Child | PCT/US2009/037402 | US | |
| Parent | PCT/US2006/060850 | Nov 2006 | US |
| Child | 11679826 | US |
