Patent Application
20090054753
This invention relates to the field of the measurement of blood analytes, and more specifically to multiple measurements of analytes such as glucose in blood that has been temporarily or permanently removed from a body.
Many 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 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 frequent 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. As research continues to show the benefits of driving patient's blood glucose levels even lower these tight glycemic control protocols have become increasingly labor intensive and complicated. Typical protocols today call for 44 blood glucose samples taken over a patient's 3 day stay in the ICU. Krinsley et al. have shown additional reductions in infections by maintaining down to a blood glucose levels in the 80 to 90 mg/dl range.
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. Currently most tight glycemic control protocols utilize fixed sampling periods. Existing protocols are typically designed with a sampling period of every 30 minutes upon admission to the intensive care unit progressing to one hour intervals as the patient stabilizes. The procurement of the blood glucose measurement is made by a manual process. Some protocols call for an increase in sampling frequency if the patient's glucose falls outside the target range. 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. Long intervals between measurements can cause a lose of tight glycemic control, or place the patient at risk. Short time intervals between measurements place significant strain on limited ICU nursing resources that already struggle to meet patient care needs.
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 in a sample. 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 an 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 (fluorescence). 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 electrodes are another example of a contact glucose sensor.
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 types of spectroscopy in widespread use: 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 radiates this energy as light. This energy can be from a variety of sources including collision and chemical reactions. Scattering spectroscopy estimates 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.
The list below describes several types of spectroscopy, but should not be considered an exhaustive 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 light sensing 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.
Some 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 resonant energy transfer, and fluorescent lifetime imaging. Laser illumination 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 this brief survey, there are multiple methods and means of spectroscopic techniques that can be applied to measuring analytes such as glucose.
Glucose measurements can be made in various media. Types of glucose measurements represented in the media include 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.
The many types of glucose sensors and glucose sensing systems that have been proposed present a range of tradeoffs. The problem of effectively integrating glucose measurements into current patient care practices remains important, however, regardless of which sensor or system is used.
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 (where the second time can be expressed as an interval after the first time, an absolute time, or a time indicated when certain patient or environmental conditions, or both, are reached or detected). The second time can be determined, as an example, 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. 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.
In other example embodiments, 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 be determined to be that predicted time. A safety margin can be imposed on the threshold, or the time, or both, if desired. The prediction of the time can be based on linear or non-linear extrapolation from previous analyte values. The mechanism for determining the next sampling time can be based on a physiological model of the patient. It can also consider information related to infusion of nutrients, insulin, glucose, or other substances. Certain changes in patient or environmental conditions can also be used to indicate that a measurement be made; e.g., a glucose measurement can be automatically initiated when a change in glucose infusion rate is made.
In some embodiments of the present invention, a second measurement can be made when a physiologic model of the patient, considering patent 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. Example physiologic models suitable for use in the present invention can include a Netter diagram model, AIDA model (http://www.2aida.net/welcome/, visited Sep. 16, 2007, incorporated herein by reference), Chase model, Bergman model, compartment model with differential equations, insulin pharmacokinetics and distribution model, glucose pharmacokinetics and distribution model, meal model, glucose/insulin pharmacodynamic model, and insulin secretion and kinetics model, or a combination of two or more of the preceding. A model can be applied and a second time determined as of the preceding measurement, or the model can be updated as time lapses or patient or environmental conditions change. The model can be adjusted to better fit the patient by considering previous combinations of patient and environmental conditions and measured analyte values.
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.
The present invention also provides apparatuses useful for determining analyte values such as blood glucose concentrations. 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.
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, example embodiments, 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.
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 (where the second time can be expressed as an interval after the first time, an absolute time, or a time indicated when certain patient or environmental conditions, or both, are reached or detected). The second time can be determined, as an example, 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. The invention 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.
In other example embodiments, 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 be determined to be that predicted time. A safety margin can be imposed on the threshold, or the time, or both, if desired. The prediction of the time can be based on linear or non-linear extrapolation from previous analyte values. The mechanism for determining the next sampling time can be based upon a physiological model of the patient. It can also consider information related to infusion of nutrients, insulin, glucose, or other substances. Certain changes in patient or environmental conditions can also be used to indicate that a measurement be made; e.g., a glucose measurement can be automatically initiated when a change in glucose infusion rate is made.
In some embodiments of the present invention, a second measurement can be made when a physiologic model of the patient, considering patent 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. Example physiologic models suitable for use in the present invention can include a Netter diagram model, AIDA model, Chase model, Bergman model, compartment model with differential equations, insulin pharmacokinetics and distribution model, glucose pharmacokinetics and distribution model, meal model, glucose/insulin pharmacodynamic model, and insulin secretion and kinetics model, or a combination of two or more of the preceding. A model can be applied and a second time determined as of the preceding measurement, or the model can be updated as time lapses or patient or environmental conditions change. The model can be adjusted to better fit the patient by considering previous combinations of patient and environmental conditions and measured analyte values.
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.
The present invention also provides apparatuses useful for determining analyte values such as blood glucose concentrations. 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.
The present invention comprises methods and apparatuses that can provide measurement of analytes such as glucose at intervals determined based on characteristics of the patient. Varying the sampling interval based on the patient's condition can allow close control of the patient's glucose without requiring an excessive number of measurements. A glucose measurement can be made, and a “next-sample-condition” defined based on environmental conditions (e.g., ventilation state, infusion rates, etc.), the patient's condition (e.g., recent glucose level, past response, etc.), or a combination thereof. When the next-sample-condition is satisfied, then a subsequent glucose measurement can be made. Using such a next-sample-condition allows the number of samples taken to be reduced while still maintaining tight and safe control of an analyte such glucose.
As used in connection with the present invention, “the patient's condition” or “patient condition” includes without limitation parameters of the patient such as physiological parameters like blood pressure, previous glucose measurements; previous response to glucose or insulin or medication or other treatment; presence, stage, or type of diabetes, other physical conditions; previous responses to the preceding or to environmental conditions. As used in connection with the present invention, “environmental conditions” includes without limitation controlled parameters such as medication or nutrient infusion rates, state of other treatments such as ventilators; temperature or humidity.
The present invention is particularly useful in combination with a measurement system that can automatically measure glucose, for example such as those described in U.S. patent application Ser. No. 11/352,956 “Apparatus and methods for analyzing body fluid samples”, filed Feb. 13, 2006; Ser. No. 11/316,407 “Apparatus and methods for analyzing body fluid samples”, filed Dec. 21, 2005; Ser. No. 10/850,646 “Analyte determinations”, filed May 21, 2004; Ser. No. 11/679,826 “Blood Analyte Determinations”, filed Feb. 27, 2007; Ser. No. 11/679,837 “Analyte Determinations”, filed Feb. 28, 2007; Ser. No. 11/679,839 “Analyte Determinations”, filed Feb. 28, 2007; Ser. No. 11/679,835 “Analyte Determinations”, filed Feb. 27, 2007; each of which is incorporated herein by reference. Such systems, combined with the present invention, can provide measurements whose frequency is adjusted to meet clinical requirements. By automatically determining the sampling time and by having the ability to procure a blood glucose measurement automatically, the system can ensure the time period associated with undetected hyper or hypo glycemia is minimized. As the patient becomes likely to approach the target glucose limits, the system increases its sampling frequency such that the time a patient spends outside of the target zone without a glucose measurement to allow corrective action is minimized. The ability of the system to both determine the next sampling time as well as perform a measurement automatically results in a system that is safer than a system totally dependent upon manual intervention by the care provider for each measurement.
Utilization of a measurement frequency greater than required for sufficient control results in a measurement rate that can be undesirable, as well. Generally, there is some cost or risk associated with each measurement event. As examples, many measurement systems require some patient blood loss for each measurement, so too frequent measurements can lead to undesirable blood loss. Some measurement systems result in saline infused into the patient with each measurement, so too frequent measurements can lead to undesirable blood dilution with saline. Some measurement systems require saline to clean or flush parts of the system, so too frequent measurements can cause added expense associated with consumption and replacement of saline and disposing of waste. Some measurement systems require disposable strips or enzymes for each measurement, so too frequent measurements can cause added expense associated with consumption of strips or enzymes. Exposure of the blood access system to blood products can risk aggregating, clotting, or system occlusions, so too frequent measurements can increase the risk of an adverse occurrence. Accessing a blood sample for measurement can risk infection, so too frequent measurements can increase the overall risk of infection. In current clinical practice the cost and risk associated with obtaining a glucose measurement is high, so in some hospitals measurements are made less frequently than desirable resulting in compromised patient care and safety. However, the risk of poor glucose control is known, so in other conditions measurements can be made more frequently than required for patient care and safety resulting in the risks described above.
A patient's systemic glucose value and the rate of change of the systemic glucose value result from a complex interaction among many internal and external factors. 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. The glucose level can be utilized as a parameter to determine the next sampling time.
Rate of glucose change: if the patient's blood glucose is changing rapidly the glucose may quickly exceed a target limit. The rate of glucose change can be utilized as a parameter to determine the next sampling time.
Insulin dosing history: the insulin dosing history will influence the expected rate of change and the level of blood glucose. Insulin dosing history can be utilized as a parameter to determine the next sampling time.
Caloric intake history: the caloric intake history will influence the expected change and magnitude of the blood glucose. Changes in the amount of calories administered, or rate at which calories are administered, to the patient either by mouth or via the blood system can be utilized as a parameter to determine the next sampling time.
Medications: medications can influence the body's regulation of blood glucose and response to insulin. Medication information can be utilized as a parameter to determine the next sampling time.
Insulin sensitivity: insulin sensitivity is a general measure of the body's response to insulin dosing. This factor can change as the patient's physiological status changes and can be useful in determining the patient's response to therapy. The patient's insulin sensitivity can be determined in various ways, for example by input from a care provider, by inference from other conditions, or by determination from previous insulin dosing and glucose measurement information. Insulin sensitivity can be utilized as a parameter to determine the next sampling time.
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. The target glucose range can be utilized as a parameter to determine the next sampling time.
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. This period is typically one with high rates of glucose change and can require more frequent monitoring. Information regarding the duration of time in the intensive care unit can be utilized as a parameter to determine the next sampling time.
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. The estimated parameters of this model (including insulin sensitivity) can be utilized to determine the next sampling time.
The next sampling time can be determined as an interval from the previous sampling time. For example, the invention can determine that the next glucose measurement should be made 30 minutes after the preceding measurement. The measurement system can simply wait until 30 minutes have passed and then perform the measurement. The next sampling time can also be determined based on patient conditions or environmental conditions as they change. For example, the invention can determine that the next glucose measurement should be made within 10 minutes of when the insulin infusion rate changes. The next sampling time can also be determined by a combination of the above methods, so that the time since last glucose measurement is a parameter to be considered along with other parameters. For example, the invention can determine that the next glucose measurement should be made 45 minutes after the preceding measurement, but an intervening parameter chance (e.g., nutrient infusion rate change) can indicate an earlier or later time for the next measurement. The next sampling time can be determined to be a time that will provide a glucose measurement before the patient's glucose is anticipated to be outside of a target range, allowing for adjustments of therapy to maintain the desired glucose value.
A method according to the present invention can determine a measurement time based only on past glucose measurements and target glucose range.
In
While only two measurements and straight line interpolation were used in the discussion of
The determination of a next measurement time, described previously in the context of mathematical determinations based on previous values, can also be based on a physiological model of the patient's response to patient conditions, environmental conditions, or a combination thereof.
The preceding modeling methods can be updated, trained or adjusted by using actual values obtained by the measurement system. For example, the actual measured glucose value can be compared to the value predicted by a physiologic model and a variety of model parameters adjusted as needed. Experience with the response of a particular patient can thereby be used to further improve the safety of the system while also reducing unnecessarily frequent sampling.
Example Embodiment.
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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.
This application is related to U.S. provisional application 60/791,719, filed Apr. 12, 2006, and to U.S. provisional application 60/737,254, filed Nov. 15, 2006, each of which is incorporated herein by reference.
