Abstract:
A method and system for determining a hyper or hypoglycemic state in a diabetic patient using acetone concentration in exhaled breath by means of a nasal device containing an acetone sensor. When a hyper or hypoglycemic state is detected, an alarm is issued. The alarm can be audible and/or can be sent wirelessly to a local or remote computer system.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    This invention relates to medical management of patients with diabetes. More particularly this invention relates to the field of hypoglycemia and hyperglycemia alarm systems. 
         [0002]    Individuals with diabetes carry the risk of low blood sugar, known as hypoglycemia, usually resulting from an imbalance between food, exercise, and medications, wherein a low blood sugar reaction can cause disorientation, unconsciousness, and sometimes death. If not properly monitored, an individual or medical professional may not be aware that the individual has reached a hyper or hypoglycemic state. 
         [0003]    Individuals with diabetes may also be at risk for hyperglycemia, which is an excess of sugar in the blood, and if the individual is not aware of the hyperglycemic state, serious damage and possibly death may ensue. 
         [0004]    Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes which mainly occurs in individuals with type 1 diabetes, and less often with type 2 diabetes. DKA is an acute state of severe uncontrolled diabetes that requires emergency treatment with insulin and intravenous fluids. DKA involves an increase in the serum concentration of ketones greater than 5 mEq/L, a blood glucose level of greater than 250 mg/dL although it is usually much higher), blood pH of less than 7.2, and a bicarbonate level of 18 mEq/L or less. 
         [0005]    Hypo and hyperglycemia occur in both adults and children, and the risk depends on the degree and progression of the diabetic state. The risk is especially acute during the night or at other times when the individual is sleeping. Because of the life threatening effects of nocturnal hypoglycemia in young children, parents often experience nights with severe anxiety resulting in sleep deprivation for both parents and children trying to monitor the condition.” 
         [0006]    Several automated, programmable, continuous glucose monitoring systems that use subcutaneous sensors have become available for diabetic ambulatory patients. For example, diabetic patients can now wear automated, programmable, continuous monitoring systems such as the two FDA approved glucose monitoring systems by Medtronic (Guardian REAL-Time System), and DexCom (STS Continuous Glucose Monitoring System). Those two systems are equipped with out of range patient alarms to notify the patient of large or dangerous deviations in blood glucose. The detection of hypoglycemia allows the patient to take corrective action to prevent potentially devastating complications. Choleau et al. have described the use of a continuous amperometric glucose sensor implanted in rats to predict hypoglycemia (Prevention of Hypoglycemia Using Risk Assessment With a Continuous Glucose Monitoring System, Diabetes 51:3263-3273, 2002).” 
         [0007]    The relationship between acetone in exhaled breath and diabetes has been known for some time. For example, Melker, U.S. Pat. No. 6,981,947, assigned to U. of Fla. Research Foundation, Inc., disclosed in Example III measuring endogenous and exogenous compounds such as acetones in exhaled breath, stating that “normally, the exhaled breath of a person contains water vapor, carbon dioxide, oxygen, and nitrogen, and trace concentrations of carbon monoxide, hydrogen and argon, all of which are odorless.” Melker disclosed a sensor to be used as a sensitive detector for these odorants and for the diagnosis of tooth decay, gum disease or a variety of oral, pulmonary and sinus conditions. 
         [0008]    Among the vapor phase odorant compounds detected by Mekler are acetone, which is present in diabetics who are in ketoacidosis, and the use of exhaled breath sensing as a highly sensitive method of diagnosing and following the course of treatment of this disease. 
         [0009]    However, Mekler did not teach or suggest a system for continuously or periodically measuring acetone and using the measured data to calculate and alarm a hyper or hypoglycemic state. 
         [0010]    Fu, U.S. Pat. No. 7,076,371, disclosed a non-invasive diagnostic and monitoring method and system based on odor detection. Fu&#39;s system is designed to emulate a biological nose, with numerous sensors, each with a different type of polymer responding differently to various odorant molecules. Fu taught an aerogel with a very large surface area for coating of a polymer, effectively simulating the huge number of same-type biological olfactory cells and their combined response. The polymer provides the necessary electronic and chemical coupling and a piezoelectric crystal is used for the quantitative conversion of trace amounts of odorant molecules to frequency-shift signals and allows detection of the markers of diabetes, for example. Fu also disclosed a heater incorporated with the detector to “refresh” the system so to provide confirmation of the detection of a targeted substance, which Fu said is important for minimizing false positive alarms, thus improving the general reliability of the system. Fu disclosed alternative types of sensors such as GC, HPLC, mass spectrometry, and conducting nanotubes whose conductivity changes as a result of gas absorption. Fu disclosed the relationship between acetone on a person&#39;s breath and ketoacidosis. 
         [0011]    Other systems intended primarily for use outside of a hospital setting are designed to measure temperature and moisture level of an individual&#39;s skin and to determine insulin reaction based on changes in such temperature and moisture. The “Sleep Sentry” is designed to detect hypoglycemia by monitoring temperature and moisture level of the skin of a sleeping diabetic person. If a temperature drop or increased perspiration is detected, an alarm sounds and the wearer of the device is supposed to check his or her blood sugar. 
         [0012]    Allen, et al., disclosed in U.S. 2004-0236244 A1 a hand-held medical apparatus for measuring acetone in exhaled breath as an indicator of ketosis and an aid for detection of weight loss via fat metabolism. 
         [0013]    Cranley, et al., disclosed in U.S. 2005-0084921 A1 an enzyme based sensor coupled to a detectable signal mediator for measuring acetone and methods for using the sensor to detect disease, weight loss, and bioavailability monitoring of therapeutics. 
         [0014]    Although the relationship between acetone in the breath and hypoglycemia in a diabetic is known, and methods for measuring acetone in a person&#39;s breath are known, no one has previously suggested a hypoglycemia and hyperglycemia alarm system based on changes in acetone levels in breath. 
       SUMMARY OF THE INVENTION 
       [0015]    It is an object of the present invention to provide an improved warning system for sleeping diabetics, a system which is not based on body temperature or skin moisture changes. 
         [0016]    It is another object of the present invention to provide an improvement to existing total glycemic control (TGC) procedures by continuously or periodically measuring exhaled breath of a diabetic patient and determining presence of acetone, which is indicative of a hyper or hypoglycemic state of the patient. 
         [0017]    Another object of the invention is to detect a hyper or hypoglycemic state in an individual and to provide an alarm when such state is detected. 
         [0018]    A further object of the invention is to provide a system which can be used when a diabetic individual is sleeping and at risk of hyper or hypoglycemia, which is minimally invasive and does not require blood analysis, but can detect hyper or hypoglycemia and signal an alarm when hyper or hypoglycemia is detected. 
         [0019]    In one aspect, the invention comprises (A) continuously or periodically determining acetone concentration in exhaled breath of a diabetic patient, (B) determining presence of a hyper or hypoglycemic state of the patient by calculating changes in the acetone concentration, and (C) issuing an alarm when the hyper or hypoglycemic state is determined. 
         [0020]    In another aspect, the invention comprises a system for signaling a hyper or hypoglycemic state comprising means to continually or periodically measure acetone concentration in exhaled breath comprising a sensor fluidly connected with a subject&#39;s nasal passage, for example an infrared sensor, and a programmed controller which can calculate changes in the acetone concentration in the exhaled breath based on data received from the sensor, the controller programmed to determine presence of a hyper or hypoglycemic state based on the calculated changes in acetone concentration, and an audible and/or visual alarm when the presence of a hyper or hypoglycemic state is determined. 
         [0021]    The present invention provides continuous measurement of acetone, a volatile metabolite of fat breakdown, in end-tidal gas as a proxy for hyper or hypoglycemic measurement. The invention would not substitute for periodic blood glucose determinations, but would complement glucose testing in a continuous or semi-continuous non-invasive fashion. It would help avoid hyper or hypoglycemic episodes and neurologic damage. 
         [0022]    A system which includes plastic tubing, referred to herein as a cannula, which includes one or two nasal extensions and preferably an oral extension adapted to be worn in a subject&#39;s nose and mouth, fluidly connected to a source of vacuum, which draws small amounts of exhaled breath from the subject&#39;s nose and/or mouth, can be used to obtain samples of the subject&#39;s breath. In some embodiments, a thermistor or other temperature measuring device can be used to detect a condition where the cannula extensions are no longer properly placed in the nose and/or mouth, for example if the subject pulls the cannula out while sleeping or the cannula falls out for some other reason. The temperature measuring device or thermistor is electrically connected to the controller and changes in temperature are detected and interpreted. If the temperature shows periodic physiologic variation with respect to time, then the system is properly functioning and the acetone data are valid. 
         [0023]    In some embodiments acetone detection is carried out in or adjacent to the nostrils and/or mouth and no tube, cannula, or vacuum is used. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0024]      FIG. 1  is a side perspective view of a cannula embodiment having nasal and oral extensions, with separate tubes for receiving breath exhaled through the mouth and nose. 
           [0025]      FIG. 2  is a perspective view of a cannula having a nasal module and an acetone detection module within a portion of a tube fluidly connected to the module. 
           [0026]      FIG. 3  is a perspective view of an embodiment of a system of the invention illustrating a cannula on a person&#39;s head and a module providing a source of vacuum and acetone level analysis. 
           [0027]      FIG. 4  is a perspective view of an embodiment of a system of the invention showing a cannula in place receiving breath exhaled from a person&#39;s nose, tubing, source of vacuum, an analytical module, and an alarm. 
           [0028]      FIG. 5  is a perspective view of an embodiment of a module for detecting acetone levels in exhaled breath which does not include tubing. 
           [0029]      FIG. 6  is a perspective view which illustrates an embodiment of a module for receiving and combining oral and nasal exhaled breath and for connection to a vacuum source. 
           [0030]      FIG. 7  illustrates an embodiment of a module for receiving exhaled nasal and oral breath. 
           [0031]      FIG. 8  is an embodiment of a cannula which includes nasal and oral extensions, a thermistor on the oral extension, and a connector connected to a base station which includes a source of vacuum, an infrared gas analyzer, a programmed computer which analyzes data received from the gas analyzer and the thermistor, and an alarm which can issue an audible and/or visual alarm signal. 
           [0032]      FIG. 9  is a process flow chart illustrating an embodiment of the method of the invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0033]    While the invention is capable of being carried out in various embodiments, a few illustrative embodiments will be described in the following detailed description with reference to the drawings. 
         [0034]    Referring first to  FIG. 1 , an embodiment of a system of the invention comprising a tube  11 , a module  12  having nasal projections  13 , a second module  15  fluidly attached to a mouth projection  16  and a thermistor  17  is illustrated on a person  10 . 
         [0035]    Referring now to  FIG. 2 , an embodiment with nasal projections  13  on a module  12  connected at each side to tube  11  joined at juncture  18  and including an acetone detection module  19  within a tube section  20  leading to a vacuum source  21  is illustrated in perspective. The system of  FIG. 2  is adapted to receive breath from a sleeping person, usually a diabetic, exhaled from nostrils and drawn through tube  11  and then tube section  20  by a slight negative pressure resulting from vacuum source  21  and over the acetone detection module  19  which is within tube section  20  in this embodiment. The acetone detection module is arranged to allow expired breath to flow over and around the acetone detector  19 . The acetone detector  19  comprises a modified infra red detector which is electronically connected to a controller  24  ( FIG. 4 ), which calculates acetone level changes over time and is programmed to signal an alarm indicative of a dysglycemic condition, which activates an alarm  25  ( FIG. 4 ) if the preselected threshold is exceeded. The thresholds are determined experimentally for the particular embodiment of the invention, and are adapted to signal either a hypoglycemic or hyperglycemic state. The acetone level considered normal and not exceeding a threshold may vary among individuals and so in some embodiments the threshold(s) can be set after determining non-hypoglycemic and non-hyperglycemic acetone levels for the individual. 
         [0036]      FIG. 3  is a perspective view of a sleeping individual  10  using a device of the invention having a tube  11  joined to a module  12  having nasal projections  13  and a mouth projection  14  for receiving breath exhaled through the nose and mouth and drawn through tube  11 , juncture  18 , tube section  20  and into module  22  which contains an acetone level analyzer, programmed controller, and power supply. The power supply can be either a battery or can be a transformer, in which case the device is plugged into a house power receptacle with plug  23 . In some embodiments both house power and battery backup are employed in order to continue protection if the plug is accidentally withdrawn or in the event of a power failure. 
         [0037]      FIG. 4  illustrates the person  10  with nasal projections extending directly from tube  11  rather than from a module  12  ( FIG. 1 ). Again the tube  11  is joined at a juncture  18  which forms a single tube section  20  leading to a module  22  having a vacuum source  21 , an acetone level detection module  19 , a controller  24 , a power supply  26 , and an alarm  28  which sounds when the controller calculates and thereby determines that the acetone level has exceeded a dysglycemia threshold. Various alarm embodiments are contemplated, for example a strobe light in addition to sound can be provided for use in the case of a deaf individual, or a system to make a telephone call or internet message can be provided so that an off site person can be informed when a threshold has been exceeded. 
         [0038]      FIG. 5  illustrates another embodiment of the invention which does not include tubes  11 ,  20  ( FIG. 1 ) or a vacuum source  21  ( FIG. 1 ) but rather includes nasal detectors  28  below the person&#39;s  10  nostrils and an oral detector  29  above the person&#39;s mouth, the detectors  28 ,  29  having built in acetone analytical receptors mounted on tubeless module  27  which includes a battery power supply, a controller, and electrical connection  30  to an alarm module  31  mounted on a strap  32  which extends around the person&#39;s  10  head. In this embodiment no vacuum or tubing is necessary since the acetone level is measured and determined with the receptors  28 ,  29  and module  27 . There are several chemical analyzers which are available in miniature sizes which can be used in embodiments such as the one illustrated in  FIG. 5 . 
         [0039]      FIG. 6  illustrates in perspective view partially in phantom a module  12  having a nasal projection  13  and mouth projections  16 , with a tube  20  leading to a vacuum source  21  ( FIG. 2 ). The mouth and nasal breath receptors are joined at junction  18  within module  12 . In this embodiment a thermistor  17  is used to determine temperature of breath flowing through the tubes, for example at juncture  18 , and the associated controller  24  ( FIG. 4 ) is programmed to send an alarm if the temperature of the breath in the tube system falls below a predetermined threshold which is indicative of the module not receiving actual breath but receiving room temperature air instead. This embodiment is designed to assure that the module does not become dislodged and that the person&#39;s exhaled breath is being received properly. 
         [0040]      FIG. 7  is a different embodiment of module  12  wherein the oral detector  29  is a group of holes designed to be located just outside the person&#39;s mouth rather than an extension which goes into the person&#39;s mouth. 
         [0041]      FIG. 8  illustrates an embodiment of the invention having module  12  which has a single mouth projection  16  and two nasal projections  13  for receiving exhaled breath, connected at each side of the module  12  to tube  11  which is then joined at juncture  18  and connected via tube section  20  to module  22  which contains a vacuum source, a controller, an acetone level analyzer, and power supply. 
         [0042]    The acetone analyzer  19  can be a standard infrared gas analyzer  19  set up to detect small quantities of acetone in the exhaled breath of a diabetic individual. 
         [0043]    The devices of the invention can be made in a range of sizes to fit an adult down to an infant. The device can be made of suitable plastics materials, known to those skilled in the art. The body and tubes may be made of similar or different plastics materials. 
         [0044]    When the patient is ready to sleep, a start button is pressed. The next morning the patient presses the stop button to end the breath monitoring. 
         [0045]    In the following discussion and in the claims, the terms “including” and “comprising” are used in an open-ended fashion, and thus should be interpreted to mean “including, but not limited to . . . ”. Also, the term “connect” or “connects” is intended to mean either an indirect or direct connection. Thus, if a first device connects to a second device, that connection may be through a direct connection, or through an indirect connection via other devices. The term “cannula” refers to a respiratory mask (either full or partial) that fluidly couples one or more of a patient&#39;s airways to a testing device. Thus, a “nasal cannula” couples at least one naris to the test device. Likewise, an “oral cannula” may couple to a patient&#39;s mouth. The word “cannula” alone could thus refer to a nasal cannula, an oral cannula, or a cannula that couples to both a patients nose and mouth. 
         [0046]    The controller  24  may comprise a processor which may be a microcontroller, and can have an on-board converter A/D, D/A converter, on-board random access memory (RAM), read only memory (ROM), as well as other on-board circuits, such as circuits that allow the processor to communicate to external devices. The controller  24  may actually be more than one processor but must be programmed to carry out the acetone level detection and alarm functions. The controller  24  may also drive an indicator or display device coupled to the processor, and may be coupled to on and off switches. 
         [0047]    As the person  10  inhales, at least a portion of the airflow into the nostrils is drawn through the tubing. The controller can be programmed to recognize the breathing cycles and to determine whether the airflow is due to exhaling or inhaling. 
         [0048]      FIG. 9  illustrates a method in accordance with embodiments of the invention wherein the system is placed on the person so that nasal and/or oral breath is received and the device is switched on, the system starts  33  with an system check  34  to assure that temperature data is being received from the thermistor  17  ( FIG. 1 ) and acetone levels are being received from acetone detector  19  ( FIG. 2 ), otherwise an error message  36  is issued. If the system is working normally, if the temperature drops below a predetermined threshold, a temperature alarm  37  is issued to indicate that breath is not being received properly. If temperature is normal  37  and acetone levels are within a predetermined range, then the system signals normal operation. If the measured acetone level goes outside of a predetermined range  38 , then dysglycemia alarm  39  is issued, indicating either hypoglycemia or hyperglycemia. 
         [0049]    While the invention has been described and illustrated in detail herein, various alternatives and modifications should become apparent to those skilled in this art without departing from the spirit and scope of the invention.