US20070167853A1 - System and method for monitoring health using exhaled breath - Google Patents

System and method for monitoring health using exhaled breath Download PDF

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Publication number
US20070167853A1
US20070167853A1 US11/301,911 US30191105A US2007167853A1 US 20070167853 A1 US20070167853 A1 US 20070167853A1 US 30191105 A US30191105 A US 30191105A US 2007167853 A1 US2007167853 A1 US 2007167853A1
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Prior art keywords
concentration
patient
sensors
breath
sensor
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US11/301,911
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Inventor
Richard Melker
Donn Dennis
David Bjoraker
Mark Gold
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University of Florida Research Foundation Inc
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University of Florida Research Foundation Inc
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Priority claimed from US10/054,619 external-priority patent/US7104963B2/en
Priority claimed from US10/178,877 external-priority patent/US6981947B2/en
Priority claimed from US10/788,501 external-priority patent/US20050054942A1/en
Priority claimed from PCT/US2005/006355 external-priority patent/WO2005098429A2/fr
Priority to US11/301,911 priority Critical patent/US20070167853A1/en
Application filed by University of Florida Research Foundation Inc filed Critical University of Florida Research Foundation Inc
Assigned to UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. reassignment UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOLD, MARK S., BJORAKER, DAVID G., DENNIS, DONN MICHAEL, MELKER, RICHARD J.
Priority to US11/512,856 priority patent/US8211035B2/en
Priority to EP06849923A priority patent/EP1960775A4/fr
Priority to PCT/US2006/046660 priority patent/WO2007089328A2/fr
Priority to JP2008545656A priority patent/JP2009519467A/ja
Priority to CA002633826A priority patent/CA2633826A1/fr
Publication of US20070167853A1 publication Critical patent/US20070167853A1/en
Priority to US13/246,436 priority patent/US20120016252A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
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Definitions

  • the present invention relates to non-invasive monitoring of substance/compound concentrations in blood; and more particularly, to a system and method for the determination of drug concentrations and endogenous compounds in blood utilizing a breath detection system.
  • Breath is a unique bodily fluid. Unlike blood, urine, feces, saliva, sweat and other bodily fluids, it is available on a breath to breath and therefore continuous basis. It is readily available for sampling non-invasively and because the lung receives all of the blood flow from the right side of the heart, measurements of analytes/compounds in breath correlate strongly and reproducibly with blood concentration. It is less likely to be associated with the transfer of serious infections than other bodily fluids and collection of samples is straightforward and painless.
  • exhaled breath contains 100% humidity at 37° C. (body temperature), thus it can be considered an aerosol. If the temperature of the collected sample is maintained at 37° C. or higher it will remain in this state and can be treated as a gas for compounds that are insoluble in water or readily diffuse out of water. In this instance, sensors designed to work with gaseous media would be preferable. For compounds that are highly water soluble and likely to remain in solution, the exhaled breath sample can be collected as a condensate when cooled. This liquid can then be analyzed with sensors that are designed for liquid-based analyses.
  • Compounds likely to be detectable in the gas phase typically are lipophilic (hydrophobic) such as the intravenous anesthetic agent, propofol, while compounds likely to be detected in the liquid phase are hydrophilic, such as glucose, lactic acid and perhaps even electrolytes.
  • lipophilic hydrophobic
  • hydrophilic such as glucose, lactic acid and perhaps even electrolytes.
  • an exhaled breath sample can be handled to produce a gaseous matrix for certain compounds and sensors, and a liquid matrix for others.
  • the sample can be split and a portion maintained as a gas and a portion condensed as a liquid.
  • An example of the unique characteristic of breath is the correlation between blood concentrations of drugs, both licit and illicit, and their concentration in the breath.
  • concentration of a drug in a patient's body is generally regulated both by the amount of drug ingested by the patient over a given time period, or the dosing regimen, and the rate at which the drug is metabolized and eliminated by the body.
  • compositions were delivered to patients according to standard doses based on the patient's weight.
  • pharmaceutical treatment with dosages adjusted according to blood concentration of the drug was far more efficient and demonstrated better seizure control and fewer side effects than with dosages adjusted according to patient weight.
  • TDM therapeutic drug monitoring
  • TCAs tricyclic antidepressants
  • amitriptyline imipramine
  • nortriptyline nortriptyline
  • clomipramine the tricyclics
  • SSRIs serotonin reuptake inhibitors
  • TCAs can also cause side effects due inhibition of norepinephrine reuptake and elevated norepinephrine levels. The latter can cause sedation, manic episodes, profuse sweating, palpitations, increased blood pressure, tachycardia, twitches and tremors of the tongue or upper extremities, and weight gain.
  • TCAs are no more, or may actually be slightly less effective than TCAs, TCAs are less attractive because they are more toxic than SSRIs and pose a greater threat of overdose.
  • a TCA overdose results in central nervous system and cardiovascular toxicity making the relative risk of death by overdose with a TCA 2.5 to 8.5 times that with the commercially available SSRI fluoxetine.
  • the greater danger with TCA is that side effects, as well as constant blood sampling, will persuade the patient to discontinue treatment.
  • TCA or MAOI classical antidepressant
  • Drug level testing is especially important in patients being administered medications where the margin of safety between therapeutic effectiveness and toxicity is narrow (low therapeutic index).
  • other drugs such as procainamide or digoxin, which are used to treat arrhythmias and heart failure; dilantin or valproic acid, which are used to treat seizures; gentamicin or amikacin, which are antibiotics used to treat infections and lithium which is a mainstay of treatment for dipolar disease, are examples of medications having a narrow margin of safety and therapeutic effectiveness with administration.
  • a further problem with present methods of TDM is that the concentration in the blood may not correlate with the concentration at the “effect site”. It has been found that the concentration of drug in the blood may not directly reflect the concentrations at the cellular or receptor level, where drugs exert their biological effects. The pharmacodynamics and pharmacokinetics (PD/PK) of many drugs also exhibit wide inter- and intra-individual variation. The drug concentration at the site of action relates best with clinical responses; however, it is typically difficult or impossible to measure. Although plasma drug concentrations often provide an informative and feasible measurement for defining the pharmacodynamics of medications, they do not consistently provide an accurate report of drug disposition in a patient.
  • the concentration that appears in breath correlates best with the “free” drug in the body, that is, the drug available for the therapeutic effect, thus the concentration in exhaled breath is an excellent measure of the drug fraction that is most important for the healthcare provider to know in order to make informed decisions about dose regimens.
  • the fraction of drug bound to protein and whole blood is essentially constant over a wide range of plasma and blood concentrations (i.e., free drug concentrations can be deduced from plasma and whole blood concentrations under normal circumstances) for the vast majority of subjects, various pathological circumstances can arise that make this correlation in a patient problematic (e.g., drug-drug interactions, massive blood loss and transfusion, protein losing syndromes, etc).
  • Absorption of a drug is generally dictated by route of drug administration (i.e., intravenous (IV), intramuscular (IM), subcutaneous (SC), topical, inhalation, oral, rectal, sublingual, etc.); drug factors (i.e., lipid solubility); as well as host factors (i.e., gastric emptying time). Alterations in drug absorption may affect the therapeutic effectiveness of the drug.
  • route of drug administration i.e., intravenous (IV), intramuscular (IM), subcutaneous (SC), topical, inhalation, oral, rectal, sublingual, etc.
  • drug factors i.e., lipid solubility
  • host factors i.e., gastric emptying time
  • Factors related to drug distribution include body fat, protein binding, and membranes. Because lipid soluble drugs tend to dissolve in fat, drugs can build up to very high, potentially toxic, levels in a patient with a high percentage of body fat. There are several drugs available that have a high affinity for serum proteins. Protein binding limits the therapeutic effectiveness of the drug. Membranes such as the blood brain barrier (BBB) sometimes make it difficult for the drug to be properly distributed.
  • BBB blood brain barrier
  • liver, kidney, lungs, skin, brain, and gut can all be involved in metabolizing a drug, although it most cases metabolism in the liver predominates.
  • metabolism can increase the activity, decrease the activity, or have no effect on the activity of a drug. Because metabolism of a drug differs from one patient to another, the dosage required for a drug can differ from patient to patient.
  • Routes of drug elimination include the kidney, liver, gastrointestinal tract, lungs, sweat, lacrimal fluid, and milk. All of these processes (absorption, distribution, metabolism, and excretion), which can occur at varying times after drug administration, affect the level of pharmacologically effective drug in a patient.
  • current methods for analyzing a blood sample to assess plasma drug concentrations only provides a snapshot for defining the pharmacodynamics of a drug and does not consistently provide an accurate report of drug disposition in a patient.
  • An example of the value of continuous or frequent breath monitor of drug concentrations is during anesthesia.
  • Anesthesiologists use many sophisticated and expensive devices to monitor the vital signs of and to provide respiratory and cardiovascular support for patients undergoing surgical procedures. Such monitors provide the anesthesiologist with information about the patient's physiologic status and verify that the appropriate concentrations of delivered gases are administered.
  • Anesthesia can be achieved by using either inhalational or intravenous (TV) anesthetics, or combination of both.
  • Inhalation anesthetics are substances that are brought into the body via the lungs and are distributed with the blood into the different tissues.
  • the main target of inhalation anesthetics is the brain.
  • Some commonly used inhalational anesthetics include enflurane, halothane, isoflurane, sevoflurane, desflurane, and nitrous oxide.
  • Older volatile anesthetics include ether, chloroform, and methoxyflurane.
  • IV anesthetics frequently used clinically are barbiturates, opioids, benzodiazepines, ketamine, etomidate, and propofol.
  • opioids are seldom used alone. Rather, a combination of inhalation anesthetics and intravenous drugs are administered, in a process known as “balanced anesthesia.”
  • balanced anesthesia for example, opioids are administered for analgesia, along with neuromuscular blockers for relaxation, anesthetic vapors for unconsciousness and benzodiazepines for amnesia.
  • the concentration of drug delivered is metered and the variation between patients in the depth of anesthesia resulting from known inhaled concentrations of agents is relatively narrow, permitting the anesthesiologist to confidently assume a particular level of anesthesia based on the concentration of anesthetic gas delivered.
  • Monitors used during the administration of inhalational anesthesia generally display inspired and exhaled gas concentrations.
  • a water trap, desiccant and/or filter may be used to remove water vapor and condensation from the sample.
  • Gas samples are aspirated into the monitor at a low rate to minimize the amount of gas removed from the breathing circuit and, therefore, the patient's tidal volume.
  • These gas monitors continuously sample and measure inspired and exhaled (end-tidal) concentrations of respiratory gases.
  • the monitored gases are both the physiologic gases found in the exhaled breath of patients (oxygen, carbon dioxide, and nitrogen), as well as those administered to the patient by the anesthesiologist in order to induce and maintain analgesia and anesthesia.
  • a major disadvantage of conventional gas monitors is that they only determine the concentrations of certain types of gases or a limited number of gases and most do not measure N 2 nor any medications delivered by other routes (i.e., intravenously). These monitors are also fragile, expensive and require frequent calibration and maintenance. For this reason, not all purchasers of anesthesia machines buy anesthesia gas monitors and therefore, rely on anesthesia gas vaporizers to control anesthetic gas concentration. Unfortunately, these vaporizers frequently go out of calibration and the anesthesiologist may administer too much or too little anesthesia.
  • IV anesthetics Another method of providing anesthesia includes IV anesthetics.
  • IV anesthetics At present, a major impediment to the wider use of IV anesthetics, rather than inhaled anesthetics, has been the inability to precisely determine the quantity of drug required to provide a sufficient “depth of anesthesia” without accumulating an excessive amount.
  • Propofol for example, is an agent that is widely used as a short acting IV anesthetic. Its physiochemical properties are hydrophobic and volatile. It is usually administered as a constant IV infusion in order to deliver and maintain a specific plasma concentration. Although the metabolism is mainly hepatic and rapid, there is significant inter-patient variability in the plasma concentration achieved with a known dose. However, the depth of anesthesia for a known plasma concentration is far less variable and it is therefore highly desirable to be able to evaluate plasma (or ideally free, unbound drug) concentrations in real time to accurately maintain anesthetic efficacy. [“A Simple Method for Detecting Plasma Propofol,” Akihiko Fujita, M D, et al., Feb. 25, 2000, International Anesthesia Research Society].
  • Propofol may also be monitored in urine. Metabolic processes control the clearance of propofol from the body, with the liver being the principal eliminating organ. [“First-pass Uptake and Pulmonary Clearance of Propofol,” Jette Kuipers, et al., Anesthesiology, V91, No. 6, Dec. 1999]. In a study, 88% of the dose of propofol was recovered in urine as hydroxylated and conjugated metabolites.
  • the aim of any dosage regimen in anesthesia is to titrate the delivery rate of a drug to achieve the desired pharmacologic effect for any individual patient while minimizing the unwanted toxic side effects.
  • Certain drugs such as propofol, alfentanil and remifentanil have a close relationship between free blood concentration and effect; thus, the administration of the drug can be improved by basing the dosage regimen on the pharmacokinetics of the agent. [Kenny, Gavin, Target - Controlled Infusions—Pharmacokinetics and Pharmacodynamic Variations, http://www.anaesthesiologie.med. unier Weg.de/esctaic97/a_Kenny.htm].
  • Target controlled infusion is one means for administering an IV anesthesia agent using a computer to control the infusion pump.
  • a computer with a pharmacokinetic program permits control of a desired plasma concentration of an agent, such as propofol.
  • the systems do not sample the blood in real-time, but use previously acquired population PD/PK parameters to provide a best estimate of the predicted blood concentration. However, even if TCI systems produced the exact target concentrations of blood concentration, it would not be possible to know if that concentration was satisfactory for each individual patient and for different points during the surgical procedure.
  • BIS Breast Imaging Index Monitor
  • the BIS monitor translates EEG waves from the brain into a single number—depicting the depth of anesthesia on a scale from 1 to 100.
  • neural networks have been used to classify sedation concentration from the power spectrum of the EEG signal.
  • these technologies are costly and not entirely predictive.
  • anesthesia can be achieved by using either inhalational or IV anesthetics, or combination of both (“balanced anesthesia”).
  • Monitoring techniques for inhalational and IV anesthesia differ because of the nature of the drug delivery.
  • Monitors for inhalational anesthesia delivery generally comprise systems that monitor the breathing circuit.
  • Monitors for IV anesthesia generally comprise physiologic monitoring of the patient rather than monitoring the concentration of the drug in the blood. Based on this bifurcation of monitoring systems, anesthesiologists must utilize separate systems when switching between drug delivery methods or when utilizing a combination of methods.
  • exhaled breath measurements can be used to monitor a wide range of other compounds and correlate them with blood concentrations. For instance, breath can be used to determine whether an individual has used an illicit drug. Likewise, breath can be used to determine blood glucose concentrations, thus freeing diabetics from having to perform frequent blood sticks to determine their glucose concentrations. Breath glucose can also be measured continuously in the operating room during surgery and/or the intensive care units since tight glucose control has been shown to improve wound healing and reduce the incidence of post-operative infection.
  • the breath may also be an excellent media to diagnose acute and/or chronic “stress” in humans, which can occur in various settings (e.g., injured humans stressed due to disease, accidents, or military actions, etc.; or non-injured humans stressed due to extreme/excessive exercise or environments that require an extremely high level of vigilance such as the longterm operation of military aircraft under battlefield conditions).
  • acute and/or chronic “stress” in humans can occur in various settings (e.g., injured humans stressed due to disease, accidents, or military actions, etc.; or non-injured humans stressed due to extreme/excessive exercise or environments that require an extremely high level of vigilance such as the longterm operation of military aircraft under battlefield conditions).
  • Various stress markers including those suggesting inflammation, which may appear in the breath include but are not limited to concentrations of lactic acid, ketones, cortisol, testosterone, ATP, ADP, AMP, adenosine, prostaglandins (e.g., PGF2a), leukotrienes, cytokines, interleukins, melatonin, 6-sulfatoxymelatonin, HIF-1 ⁇ , HSP70 and myogenic regulatory factors.
  • lactic acid in blood is an indicator of the severity of shock (hypoperfusion) and numerous disease states. It is usually measured intermittently by drawing blood samples. Intermittent or continuous breath measurements of lactic acid could revolutionize the care of critically ill patients in the operating room or intensive care unit. Numerous other compounds can also indicate disease states appear in breath. The ability to monitor these compounds in real-time, either intermittently or continuously without the delay of having to send specimens to a laboratory, could dramatically improve the care of hospitalized or even home care or ambulatory patients.
  • the present invention solves the needs in the art by providing a method and apparatus for non-invasive monitoring of substance/compound concentration in blood, and, more particularly to systems and methods for non-invasive monitoring of endogenous compound and/or therapeutic drug concentration in blood.
  • the systems and methods of the present invention utilize sensors that can analyze a patient's exhaled breath components to detect, quantify, and/or trend concentrations of endogenous compound markers in exhaled breath, which correlate to the endogenous compound concentration in the patient's body, in particular in blood.
  • Endogenous compound markers detectable in exhaled breath can be the endogenous compounds themselves or substances derived from the endogenous compounds (such as metabolites of endogenous compounds).
  • systems and methods are provided for the detection, quantification, and trending of delivered therapeutic drug concentration utilizing sensors that can analyze a patient's exhaled breath components.
  • Such systems and methods include: at least one supply of at least one therapeutic drug for delivery to a patient; and an expired gas sensor for analyzing the patient's breath for concentration of at least one drug or marker indicative of therapeutic drugs in the patient's bloodstream, wherein the sensor provides a signal to indicate marker concentration that corresponds to therapeutic drug concentration in the patient's bloodstream.
  • the methods of the subject invention include the steps of measuring the concentration of one or more therapeutic markers in a patient's exhaled breath. These measured markers can then be used to quantify the concentration of therapeutic drug(s) in the patient's blood as well as trend the delivered drug, and ultimately determine the PD/PK of the drug.
  • the subject invention contemplates administering to a patient a therapeutic drug, wherein the therapeutic drug contains a therapeutic drug marker that is detectable in exhaled breath by a sensor of the subject invention.
  • the therapeutic drug marker is the therapeutic drug itself or a metabolite of the drug, which is detectable in exhaled breath.
  • the blood concentration of the therapeutic drug and the exhaled concentration of the therapeutic drug marker are substantially proportional.
  • One particular application of the present invention is for predicting the depth of anesthesia utilizing a breath detection system. It has been shown that there is a good correlation between blood concentration of anesthetic agents (e.g., propofol) and depth of anesthesia.
  • the present invention provides methods and apparatuses for the detection, quantitation, and trending of intravenous (IV) and/or inhalational delivered drug concentration utilizing a breath detection system.
  • the method of the present invention will provide a more predictive method to monitor depth of anesthesia by monitoring breath rather than blood.
  • the method of the invention includes measuring both exhaled breath concentrations of IV and inhalational anesthetics, and also the circuit concentration of inhalational anesthetic gases.
  • the method includes the steps of both measuring the circuit concentration and measuring the concentration of one or more components in the patient's exhaled breath. These measured components can then be used to quantitate the concentration of anesthetics in the circuit (such as halothane, isoflurane, sevoflurane, desflurane and enflurane) and to detect, quantitate, and trend the delivered drug, and ultimately determine depth of anesthesia.
  • Emulsified perflubron is one of a class of compounds used to deliver oxygen in anemic patients as a substitute for hemoglobin.
  • a specific phase of the respiratory cycle namely the end-tidal portion of exhaled breath, is sampled to detect the concentration of a therapeutic drug marker as a measure of drug concentration levels in blood.
  • a sensor can be selected from a variety of systems that have been developed for use in collecting and monitoring exhaled breath components, particularly specific gases.
  • the sensor of the subject invention can be selected from those described in U.S. Pat. Nos. 6,010,459; 5,081,871; 5,042,501; 4,202,352; 5,971,937, and 4,734,777.
  • sensor systems having computerized data analysis components can also be used in the subject invention (i.e., U.S. Pat. No. 4,796,639).
  • Sensors of the subject invention can also include commercial devices commonly known as “artificial” or “electronic” noses or tongues to non-invasively monitor therapeutic drug blood concentration.
  • Sensors of the subject invention can include, but are not limited to, metal-insulator-metal ensemble (MIME) sensors, cross-reactive optical microsensor arrays, fluorescent polymer films, corona devices, surface enhanced Raman spectroscopy (SERS), semiconductor gas sensor technology, conductive polymer gas sensor technology, surface acoustic wave gas sensor technology, functionalized microcantilevers and immunoassays.
  • MIME metal-insulator-metal ensemble
  • SERS surface enhanced Raman spectroscopy
  • the systems of the subject invention include a reporting system capable of tracking marker concentration (remote or proximate) and providing the necessary outputs, controls, and alerts.
  • a sensor of the subject invention would be used either in a clinical setting or patient-based location during delivery of a therapeutic drug to monitor drug concentration in blood by measuring therapeutic drug marker concentration in patient exhaled breath.
  • exhaled breath detection using the systems and methods of the present invention may enable accurate evaluation of PD/PK for drug studies and/or in individual patients.
  • the preferred device of the present invention includes two parts: 1) the breathing circuit sensor and 2) the expired breath sensor.
  • the breathing circuit sensor includes a sensor having a surface exposed to the gas stream and comprises a material selectively absorptive of a chemical vapor or group of vapors.
  • the expired breath sensor includes a sensor having a surface exposed to the patient's breath and/or airway and also comprises a material selectively absorptive of a chemical vapor or group of vapors. These sensors are coupled to an analyzer(s) for producing an electrical signal indicative of the presence of the vapors. The analyzer is further operative to determine the approximate concentration of the vapors, display results, signal alarms, etc.
  • the device detects a target substance (anesthetic gases and/or physiologic gases) in both the breathing circuit and in expired breath using the following components: (a) surface-acoustic wave sensor(s) capable of detecting the presence of the target substance, wherein the sensor responds to the target substance by a shift in the resonant frequency; (b) oscillator circuit(s) having the sensor as an active feedback element; (c) frequency counter(s) in communication with the oscillator circuit(s) to measure oscillation frequency which corresponds to resonant frequency of the sensor(s); and (d) a processor for comparing the oscillation frequency with a previously measured oscillation frequency of the target substance and determining presence and concentration of the target substance therefrom.
  • a target substance as synthetic gases and/or physiologic gases
  • the device detects a target marker (anesthetic gases and/or physiologic gases) in both the breathing circuit and in expired breath using the following components: (a) sensor(s) having an array of polymers capable of detecting the presence of the target substance, wherein the sensor(s) responds to the target substance by changing the resistance in each polymer resulting in a pattern change in the sensor array; (b) a processor for receiving the change in resistance, comparing the change in resistance with a previously measured change in resistance, and identifying the presence of the target substance from the pattern change and the concentration of the substance from the amplitude.
  • the processor can include a neural network for comparing the change in resistance with a previously measured change in resistance to find a best match.
  • the invention includes a method of monitoring a patient during administration of anesthesia wherein the patient is connected to a breathing circuit.
  • a first sensor is exposed to inspired gases, wherein at least one inspired gas is an anesthetic agent; a second sensor is exposed to expired gases; one or more target substances is detected with the sensors; and concentration of the target substances is determined.
  • the invention includes an anesthetic agent delivery system for delivering balanced anesthesia to a patient through a breathing circuit and an IV which includes: (1) an anesthetic gas supply having a controller for controlling the amount of volatile anesthetic agent provided by the supply to the breathing circuit; (2) an IV anesthetic agent supply having a controller for controlling the amount of IV anesthetic agent administered to the patient intravenously; (3) an inspired gas analyzer for analyzing the concentration of anesthetic gas in the breathing circuit; (4) an expired gas analyzer for analyzing the patient's breath for concentration of at least one substance indicative of anesthetic agent concentrations in the patient's bloodstream that provides at least one signal to indicate the anesthetic agent concentration delivered to the patient; and (5) a system controller connected to each of the anesthetic supplies which receives the signal and controls the amount of anesthetic agents administered based on the signal.
  • the invention includes an apparatus for administering balanced anesthesia to a patient including: (1) at least one supply of at least one intravenous anesthetic agent; (2) intravenous delivery means for controllably delivering the intravenous anesthetic agent to the patent; (3) at least one supply of at least one inhalational anesthetic agent; (4) a breathing circuit for delivery of said inhalational anesthetic agent; (5) an inspired gas analyzer for analyzing gas in the breathing circuit for the inhalational agent; (6) an expired gas analyzer for analyzing the patient's breath for concentration of at least one substance indicative of anesthetic agents in the patient's bloodstream that provides a signal to indicate anesthetic agent concentration delivered to the patient; (7) a system controller connected to the intravenous delivery means which receives the signal and controls the amount of anesthetic agent based on the signal; and (8) a system controller connected to the breathing circuit which receives the signal and controls the amount of anesthetic agent based on the signal.
  • Another embodiment includes a device for detecting target substances in a breathing circuit including: (1) at least one surface-acoustic wave sensor capable of detecting the presence of the target substance in inspired and/or expired gas, wherein the sensor responds to the target substance by a shift in the resonant frequency; (2) an oscillator circuit having the sensor as an active feedback element; (3) a frequency counter in communication with the oscillator circuit to measure oscillation frequency which corresponds to resonant frequency of the sensor; and (4) a processor for comparing the oscillation frequency with a previously measured oscillation frequency of the target substance and determining presence and concentration of the target substance therefrom.
  • Another embodiment includes a device for detecting target substances in a breathing circuit including: (1) a sensor having an array of polymers capable of detecting the presence of the target substance in inspired and/or expired gas, wherein the sensor responds to the target substance by changing the resistance in each polymer resulting in a pattern change in the sensor array; (2) a processor for receiving the change in resistance, comparing the change in resistance with a previously measured change in resistance, and identifying the presence of the target substance from the pattern change and the concentration of the substance from the amplitude.
  • exhaled breath detection using the method of the present invention may also evaluate PD/PK for both drug studies and in individual patients. Moreover, it may be used to sense endogenous compounds such as glucose, ketones, lactic acid and electrolytes, which are normally found in blood.
  • the invention also includes a method of determining the rate of washout of a target substance (such as anesthetic gases or other drugs) by (a) obtaining a sample of expired breath at a first interval; (b) analyzing the sample with sensor technology to determine the concentration of the substance; (c) obtaining at least one additional sample of expired breath at a later interval; (d) analyzing said additional sample with sensor technology to determine the concentration of said substance; and (e) comparing the concentration of the first sample with the concentration of additional samples to determine rate of washout of the target substance.
  • a target substance such as anesthetic gases or other drugs
  • monitoring of therapeutic drug marker and/or endogenous compound marker concentration is conducted continuously using a system of the invention. In another embodiment of the invention, monitoring of therapeutic drug marker and/or endogenous compound marker concentration is conducted intermittently using a system of the invention.
  • Another object of the present invention is to non-invasively monitor substance concentration (such as endogenous compound blood concentration) by monitoring substance or substance marker concentrations in exhaled breath using sensors that analyze exhaled breath components.
  • Exhaled breath detection using the method of the present invention may be used to sense endogenous compounds such as glucose, ketones, lactic acid, and electrolytes that are normally found in blood. These compounds could be monitored intermittently or continuously in a wide range of environments. Small handheld portable equipment could be used by patients in the home, at work, in nursing homes or while they are ambulatory, while other devices could be designed for continuous monitoring in the operating room, intensive care units and in other areas of hospitals or other healthcare facilities such as clinics, doctors offices where this capability would be valuable.
  • a resulting advantage of the subject invention is the ability to monitor such substance and/or therapeutic drug concentration in a more cost effective and frequent manner than current methods, which involve drawing blood samples and transferring the blood samples to a laboratory facility for analysis.
  • the subject invention enables the user to immediately and continuously monitor therapeutic drug and/or endogenous compound concentration levels in a patient's blood stream to monitor patient health, whether in a clinical setting or via known forms of communication if the patient is located at a remote location.
  • the systems and methods of the subject invention can be used in place of the invasive practice of drawing blood to measure concentration.
  • FIG. 1 shows a capnogram of a single respiratory cycle and a capnogram of several breaths from a patient with obstructive lung disease.
  • FIG. 2 shows a gas sensor chip, which may be utilized as the sensor for the present invention.
  • FIG. 3 shows the FT-IR signal for propofol.
  • FIG. 4 shows an example of measuring expired breath of a patient utilizing a sensor.
  • FIG. 5 a shows the characteristic signature of propofol.
  • FIG. 5 b shows a propofol relative breath concentration profile of a patient.
  • FIG. 6 a shows the unique signature of Isoflurane derived from a SAW sensor.
  • FIG. 6 b shows the unique signature of Sevoflurane derived from a SAW sensor.
  • FIGS. 7 a and 7 b illustrate the blood (8a) and breath (8b) concentrations of glucose over time after the ingestion of a 100 gm glucose solution.
  • the present invention provides systems and methods for non-invasive monitoring of substances in blood by analyzing a patient's exhaled breath components.
  • Substances in blood that can be monitored by analyzing exhaled breath components include, but are not limited to, endogenous compounds, such as glucose, ketones, lactic acid, prostaglandins, leukotrienes, cortisol, and electrolytes, and therapeutic drugs, including IV and/or inhalation anesthetics for detecting the depth of anesthesia and a wide range of licit and illicit drugs.
  • the breath concentration of at least one endogenous compound marker is analyzed using sensor technology.
  • the endogenous compound marker can be the endogenous compound itself or derived from the endogenous compound, such as a metabolite of the endogenous compound.
  • the concentration of an endogenous compound marker in breath is proportionate to the concentration of the corresponding endogenous compound in blood.
  • therapeutic drug refers to a substance used in the diagnosis, treatment, or prevention of a disease or condition, wherein the concentration of the therapeutic drug in a patient's blood stream must be monitored to ensure the therapeutic drug level is within a clinically effective range.
  • a therapeutic drug of the present invention includes anesthetic agents.
  • an endogenous compound marker is either the endogenous compound itself or a compound derived directly from the endogenous compound (such as a metabolite of the endogenous compound).
  • Therapeutic drug markers are the therapeutic drug itself, or derived either directly from the therapeutic drug (such as a metabolite) or from an additive combined with the therapeutic drug prior to administration.
  • Such therapeutic drug markers preferably include olfactory markers (odors) as well as other substances and compounds, which may be detectable by sensors of the subject invention.
  • Halogenated compounds i.e. fluorinated drugs or markers
  • Some of these compounds are used as propellants for delivery of drugs via the pulmonary route, such as metered dose inhalers and therefore are known to be safe and are FDA approved.
  • the technologies most often used to detect Freon leaks include: Negative Ion Capture, Heated Sensor/Ceramic Semiconductor, Infrared Absorption, and TIF TIFXP-1A Negative Corona Leak Detector.
  • Many drugs are fluorinated and metabolites are often extremely volatile and detectable in exhaled breath. Numerous such compounds are available that could be used as markers and could be added as excipients during the manufacture of drugs
  • a “patient,” as used herein, describes an organism, including mammals, from which exhaled breath samples are collected in accordance with the present invention.
  • Mammalian species that benefit from the disclosed systems and methods for therapeutic drug monitoring include, and are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals (e.g., pets) such as dogs, cats, mice, rats, guinea pigs, and hamsters.
  • substances detectable in exhaled breath using the systems and methods of the invention include those that may be found in breath gas, breath condensate (liquid phase), respiratory droplet, breath evaporate, water vapor, and/or bronchial or alveolar aerosols.
  • pharmacodynamics refers to the interaction (biochemical and physiological) of a therapeutic drug with constituents of a patient body as well as the mechanisms of drug action on the patient body (i.e., drug effect on body).
  • pharmacokinetics refers to the mathematical characterization of interactions between normal physiological processes and a therapeutic drug over time (i.e., body effect on drug). Certain physiological processes (absorption, distribution, metabolism, and elimination) will affect the ability of a drug to provide a desired therapeutic effect in a patient. Knowledge of a drug's pharmacokinetics aids in interpreting drug blood stream concentration and is useful in determining pharmacologically effective drug dosages.
  • Constant administration refers to the administration of a therapeutic drug marker suitable for use with the systems and methods of the invention (administration of a therapeutic drug) for monitoring therapeutic drug levels in blood stream.
  • a therapeutic drug marker can be provided in admixture with a therapeutic drug, such as in a pharmaceutical composition; or the marker and therapeutic drug can be administered to a patient as separate compounds, such as, for example, separate pharmaceutical compositions administered consecutively, simultaneously, or at different times.
  • the marker and the therapeutic drug are administered separately, they are administered within sufficient time from each other so that the concentration of the marker in exhaled breath is an accurate indicator of the concentration of therapeutic drug in the blood stream.
  • aptamer refers to a non-naturally occurring oligonucleotide chain that has a specific action on a therapeutic drug marker.
  • Aptamers include nucleic acids that are identified from a candidate mixture of nucleic acids.
  • aptamers include nucleic acid sequences that are substantially homologous to the nucleic acid ligands isolated by the SELEX method. Substantially homologous is meant a degree of primary sequence homology in excess of 70%, most preferably in excess of 80%.
  • the “SELEXTM” methodology involves the combination of selected nucleic acid ligands, which interact with a target marker in a desired action, for example binding to an olfactory marker, with amplification of those selected nucleic acids.
  • a desired action for example binding to an olfactory marker
  • Optional iterative cycling of the selection/amplification steps allows selection of one or a small number of nucleic acids, which interact most strongly with the target marker from a pool, which contains a very large number of nucleic acids. Cycling of the selection/amplification procedure is continued until a selected goal is achieved.
  • the SELEX methodology is described in the following U.S. patents and patent applications: U.S. patent application Ser. No. 07/536,428 and U.S. Pat. Nos. 5,475,096 and 5,270,163.
  • the term “pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally compatible with the other ingredients of the composition, not deleterious to the patient, and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier” as used in the specification and claims includes both one and more than one such carrier.
  • the exhalation gas stream comprises sequences or stages.
  • the gas representative thereof coming from an anatomically inactive (deadspace) part of the respiratory system, in other words, from the mouth and upper respiratory tracts.
  • the gas is a mixture of deadspace and metabolically active gases.
  • the plateau phase which comprises the last portion of the exhaled breath, nothing but deep lung gas, so-called alveolar gas is present. This gas, which comes from the alveoli, is termed end-tidal gas.
  • exhaled gas from any specific phase of the respiratory cycle can be sampled to detect for the presence of target markers as indicators of therapeutic drug and/or endogenous compound concentration in the patient.
  • sensor technology as described herein can be applied to exhalation samples drawn from the initial phase, or the end-tidal (late plateau) phase.
  • the exhaled breath sample is collected at end-tidal breathing.
  • in-line sampling Single or multiple samples collected by the known in-line (or mainstream) sampling method are preferable, but if sensor acquisition time is reduced, side stream sampling may be used.
  • a sensor of the subject invention is placed proximal to the ET tube directly in the gas stream. In the latter, samples are collected through an adapter at the proximal end of an endotracheal (ET) tube and drawn through thin bore tubing to a sensor of the subject invention.
  • the sensor is placed in a sampling chamber positioned within the patient's gas stream.
  • samples can be taken throughout the exhalation phase of respiration and an average value determined and correlated with blood concentration.
  • exhaled gas may be collected on successive cycles.
  • the upper frame demonstrates a capnogram of a single respiratory cycle.
  • samples are taken at the point labeled “end-tidal PCO 2 ” which reflects the CO 2 concentration in the lung.
  • the lower frame shows a capnogram of several breaths from a patient with obstructive lung disease. Again the end-tidal sample correlated best with blood concentration.
  • a VaporLabTM brand instrument is used to collect and analyze exhaled breath samples.
  • the VaporLabTM instrument is a hand-held, battery powered SAW-based chemical vapor identification instrument suitable for detecting components in exhaled breath samples in accordance with the present invention.
  • This instrument is sensitive to volatile and semi-volatile compounds using a high-stability SAW sensor array that provides orthogonal vapor responses for greater accuracy and discrimination.
  • this instrument communicates with computers to provide enhanced pattern analysis and report generation.
  • this instrument includes neural networks for “training” purposes, i.e., to remember chemical vapor signature patterns for fast, “on-the-fly” analysis.
  • samples are collected at the distal end of an ET tube through a tube with a separate sampling port. This may improve sampling by allowing a “cleaner—(less deadspace)” sample during each respiratory cycle.
  • the concentration of a therapeutic drug in a patient body is regulated by the amount of the drug administered over a given time period and the rate at which the agent is eliminated from the body (metabolism).
  • the present invention provides the steps of administering a therapeutic drug to a patient and analyzing patient exhaled breath for concentration of therapeutic drug markers such as unbound substances, active metabolites, or inactive metabolites associated with the therapeutic drug, after a suitable time period.
  • the marker concentration indicates a characteristic of metabolism of the drug in the patient.
  • Methods of the subject invention may further include the use of a flow sensor to detect starting and completion of exhalation.
  • the method further includes providing results from the analysis and communicating to the user or patient the blood concentration of the therapeutic drug.
  • results from analysis can be communicated immediately upon sampling exhaled gases.
  • the subject invention enables the immediate monitoring of therapeutic drug levels in a patient's blood stream.
  • immediate monitoring refers to sampling and analysis of exhaled gases from a patient for target markers substantially completely within a short time period following administration of a therapeutic drug (i.e., generally within a few minutes to about 24 hours).
  • a system and/or method of the invention can be provided to a patient taking a therapeutic drug for intermittent or continuous monitoring of therapeutic drug concentrations (or endogenous compound markers) in the blood stream.
  • the monitoring system and method of the subject invention can be administered to a patient taking a therapeutic drug on an hourly, daily, weekly, monthly, or even annual basis. Further, additional monitoring can be administered to a patient when an additional therapeutic drug is prescribed.
  • a CPU may be provided as a data processing/control unit for automatically detecting the signal from the flow sensor to control sampling of exhaled breath.
  • the CPU may further provide to the user/patient the appropriate dosage of the therapeutic drug to be delivered based on analysis of trends in therapeutic drug blood concentration.
  • the CPU may further provide the analysis and control of the infusion pump or other administering means for anesthetic agents.
  • the present invention provides means for automatically adjusting and administering the appropriate dosage of a therapeutic drug, based on blood concentration levels, to a patient.
  • a CPU is provided for analysis and control of dosage adjusting and administering means.
  • an infusion pump is used, wherein the CPU provides analysis and control of the infusion pump.
  • Concentration in the blood of therapeutic drug markers may indicate when the patient is receiving a high dose (i.e., toxic dose), a low dose (i.e., ineffective dose), or effective (i.e., appropriate) dose of the therapeutic drug.
  • a high dose i.e., toxic dose
  • a low dose i.e., ineffective dose
  • effective dose i.e., appropriate dose of the therapeutic drug.
  • knowledge of the exhaled breath concentration allows the user to know if the drug is accumulating in the blood, possibly leading to dangerously toxic levels of the drug, or that the concentration is falling, possibly leading to an inadequate dose of the drug.
  • Monitoring changes in therapeutic drug blood concentration in accordance with the subject invention are, therefore, useful.
  • the exhalation air is measured for marker (such as endogenous compound, therapeutic drug, free agent, and/or metabolite) concentration either continuously or intermittently/periodically. From the exhalation air is extracted at least one measured marker concentration value.
  • marker such as endogenous compound, therapeutic drug, free agent, and/or metabolite
  • Numerous types of breath sampling apparatuses can be used to carry out the method of the present invention.
  • the breath sampling apparatus includes a conventional flow channel through which exhalation air flows.
  • the flow channel is provided with a sensor of the subject invention for measuring marker concentration.
  • necessary output elements may be included with the breath sampling apparatus for delivering at least a measured concentration result to the user, if necessary.
  • the level of concentration is measured, it is given numerical value (for example, 50 on a scale of 1 to 100). Should the concentration fall below that value, the new value would be indicative of a decrease in concentration. Should the concentration increase beyond that value, the new value would be indicative of an increase in concentration.
  • This numerical scale would allow for easier monitoring of changes in concentration. The numerical scale would also allow for easier translation into control signals for alarms, outputs, charting, and control of external devices (e.g., infusion pump). The upper and lower limits could be set to indicate thresholds such as from ineffective to dangerous therapeutic drug levels.
  • the invention preferably utilizes gas sensor technology, such as commercial devices known as “artificial” or “electronic” tongues or noses, to non-invasively monitor marker concentration in exhaled breath ( FIG. 2 ).
  • Gas sensor technology such as commercial devices known as “artificial” or “electronic” tongues or noses, to non-invasively monitor marker concentration in exhaled breath ( FIG. 2 ).
  • Electronic noses have been used mostly in the food, wine, and perfume industry where their sensitivity makes it possible to distinguish between odorous compounds. For example, electronic noses have been useful in distinguishing between grapefruit oil and orange oil in the perfume industry and identify spoilage in perishable foods before the odor is evident to the human nose.
  • a genitourinary clinic has utilized an electronic nose to screen for, and detect bacterial vaginosis, with a 94% success rate after training (Chandiok S, et al., “Screening for bacterial vaginosis: a novel application of artificial nose technology,” Journal of Clinical Pathology, 50(9):790-1 (1997)).
  • Specific bacterial species can also be identified with the electronic nose based on special odors produced by the organisms (Parry A D et al., “Leg ulcer odor detection identifies beta-haemolytic streptococcal infection,” Journal of Wound Care, 4:404-406 (1995)).
  • a number of patents which describe gas sensor technology that can be used in the subject invention include, but are not limited to, the following: U.S. Pat. Nos. 5,945,069; 5,918,257; 4,938,928; 4,992,244; 5,034,192; 5,071,770; 5,145,645; 5,252,292; 5,605,612; 5,756,879; 5,783,154; and 5,830,412.
  • sensors suitable for the present invention include, but are not limited to, metal-insulator-metal ensemble (MIME) sensors, cross-reactive optical microsensor arrays, fluorescent polymer films, surface enhanced raman spectroscopy (SERS), diode lasers, selected ion flow tubes, metal oxide sensors (MOS), non-dispersive infrared spectrometer, bulk acoustic wave sensors, calorimetric tubes, functionalized microcantilevers and infrared spectroscopy.
  • MIME metal-insulator-metal ensemble
  • SERS surface enhanced raman spectroscopy
  • MOS metal oxide sensors
  • non-dispersive infrared spectrometer bulk acoustic wave sensors
  • calorimetric tubes functionalized microcantilevers and infrared spectroscopy.
  • Recent developments in the field of detection that can also be used as sensor for the subject invention include, but are not limited to, gas chromatography, semiconductive gas sensors, mass spectrometers (including proton transfer reaction mass spectrometry), and infrared (IR) or ultraviolet (UV) or visible or fluorescence spectrophotometers (i.e., non-dispersive infrared spectrometer).
  • gas chromatography which consists of a method of selective detection by separating the molecules of gas compositions, maybe used as a means for analyzing markers in exhaled breath samples.
  • sensors for detecting/quantifying markers utilize a relatively brief detection time of around a few seconds.
  • Other recent gas sensor technologies contemplated by the present invention include apparatuses having conductive-polymer gas-sensors (“polymeric”), aptamer biosensors, amplifying fluorescent polymer (AFP) sensors, and apparatuses having surface-acoustic-wave (SAW) gas-sensors.
  • the conductive-polymer gas-sensors (also referred to as “chemoresistors”) have a film made of a conductive polymer sensitive to the molecules of odorous substances. On contact with target marker molecules, the electric resistance of the sensors changes and the measurement of the variation ofthis resistance enables the concentration of the markers to be determined.
  • An advantage of this type of sensor is that it functions at temperatures close to room temperature. Different sensitivities for detecting different markers can be obtained by modifying or choosing an alternate conductive polymer.
  • Polymeric gas sensors can be built into an array of sensors, where each sensor is designed to respond differently to different markers and augment the selectivity of the therapeutic drug markers.
  • a sensor of the subject invention can comprise of an array of polymers, (i.e., 32 different polymers) each exposed to a marker. Each of the individual polymers swells differently to the presence of a marker, creating a change in the resistance of that membrane and generating an analog voltage in response to that specific marker (“signature”). The normalized change in resistance can then be transmitted to a processor to identify the type, quantity, and quality of the marker based on the pattern change in the sensor array. The unique response results in a distinct electrical fingerprint that is used to characterize the marker.
  • the pattern of resistance changes of the array is diagnostic of the marker in the sample, while the amplitude of the pattern indicates the concentration of the marker in the sample.
  • the sensor can be attached to a computer.
  • the results can be displayed on the computer screen, stored, transmitted, etc.
  • a data analyzer can compare a pattern of response to previously measured and characterized responses from known substances. The matching of those patterns can be performed using a number of techniques, including neural networks.
  • a neural network can establish a pattern that is unique to that substance and subsequently learns to recognize that substance.
  • the particular resistor geometries are selected to optimize the desired response to the particular substance being sensed.
  • the sensor of the present invention is a self-calibrating polymer system suitable for liquid or gas phase biological solutions for detecting a variety of target markers simultaneously.
  • Another sensor of the invention can be provided in the form of an aptamer.
  • the SELEXTM (Systematic Evolution of Ligands by EXponential enrichment) methodology is used to produce aptamers that recognize therapeutic drug markers with high affinity and specificity.
  • Aptamers produced by the SELEX methodology have a unique sequence and the property of binding specifically to a desired marker.
  • the SELEX methodology is based on the insight that nucleic acids have sufficient capacity for forming a variety of two- and three-dimensional structures and sufficient chemical versatility available within their monomers to act as ligands (form specific binding pairs) with virtually any chemical compound, whether monomeric or polymeric.
  • therapeutic drug markers of any size or composition can thus serve as targets for aptamers. See also Jayasena, S., “Aptamers: An Emerging Class of Molecules That Rival Antibodies for Diagnostics,” Clinical Chemistry, 45:9, 1628-1650 (1999).
  • aptamer biosensors can be utilized in the present invention for detecting the presence of markers in exhaled breath samples.
  • aptamer sensors are composed of resonant oscillating quartz sensors that can detect minute changes in resonance frequencies due to modulations of mass of the oscillating system, which results from a binding or dissociation event (i.e., binding with a target therapeutic drug marker).
  • molecular beacons and molecular beacon aptamers (MBA) employ fluorescence resonance energy transfer based methods to provide fluorescence signal increases in the presence of particular target sequences. See also, Stojanovic, Milan N., de Prada, Paloma, and Landry, Donald W., “Aptamer-Based Folding Fluorescent Sensor for Cocaine” J. Am. Chem. Soc. 2001, 123, 4928-4931 (2001); Jayasena, Sumedha D., “Aptamers: An Emerging Class of Molecules That Rival Antibodies of Diagnostics, Clinical Chemistry 45:9, 1628-1650 (1999).
  • Amplifying fluorescent polymer (AFP) sensors may be utilized in the present invention for detecting the presence of therapeutic drug markers and/or endogenous compound markers in exhaled breath samples.
  • AFP sensors are extremely sensitive and highly selective chemosensors that use amplifying fluorescent polymers.
  • target markers bind to thin films of the polymers, the fluorescence of the film decreases.
  • a single molecule binding event quenches the fluorescence of many polymer repeat units, resulting in an amplification of the quenching.
  • the binding of markers to the film is reversible, therefore the films can be reused.
  • SAW sensors oscillate at high frequencies and generally have a substrate, which is covered by a chemoselective material.
  • the substrate is used to propagate a surface acoustic wave between sets of interdigitated electrodes (i.e., to form a transducer).
  • the chemoselective material is coated on the transducer.
  • a marker interacts with the chemoselective material coated on the substrate, the interaction results in a change in the SAW properties, such as the amplitude of velocity of the propagated wave.
  • the detectable change in the characteristic wave is generally proportional to the mass load of the marker(s) (i.e., concentration of the marker in exhaled breath, which corresponds to the concentration of the therapeutic drug and/or endogenous compound in the blood stream).
  • Certain embodiments of the invention use known SAW devices, such as those described in U.S. Pat. Nos. 4,312,228 and 4,895,017, and Groves W. A. et al., “Analyzing organic vapors in exhaled breath using surface acoustic wave sensor array with preconcentration: Selection and characterization of the preconcentrator adsorbent,” Analytica Chimica Acta, 371:131-143 (1988).
  • AWA bulk acoustic wave
  • IME interdigitated microelectrode
  • OW optical waveguide
  • electrochemical sensors electrochemical sensors
  • electrically conducting sensors include bulk acoustic wave (BAW) devices, plate acoustic wave devices, interdigitated microelectrode (IME) devices, optical waveguide (OW) devices, electrochemical sensors, and electrically conducting sensors.
  • BAW bulk acoustic wave
  • IME interdigitated microelectrode
  • OW optical waveguide
  • the senor of the invention is based on surface acoustic wave (SAW) sensors.
  • SAW sensors preferably include a substrate with piezoelectric characteristics covered by a polymer coating, which is able to selectively absorb target markers.
  • SAW sensors oscillate at high frequencies and respond to perturbations proportional to the mass load of certain molecules. This occurs in the vapor phase on the sensor surface.
  • the senor of the invention is based on a SAW sensor of Stubbs, D. et al. (see Stubbs, D. et al., “Investigation of cocaine plumes using surface acoustic wave immunoassay sensors,” Anal Chem., 75(22):6231-5 (November 2003) and Stubbs, D. et al., “Gas phase activity of anti-FITC antibodies immobilized on a surface acoustic wave resonator device,” Biosens Bioelectron, 17(6-7):471-7 (2002)).
  • the sensor of the subject invention can include a two-port resonator on ST-X quartz with a center frequency of 250 MHz.
  • a temperature compensated surface acoustic wave (SAW) is generated via an interdigital transducer.
  • Antibodies specific to a target marker are then attached to the electrodes (i.e., 1.5 micron wide) on the sensor device surface via protein cross linkers.
  • the electrodes i.e., 1.5 micron wide
  • protein cross linkers In the vapor phase on the sensor surface, when target markers are present, a change in frequency occurs to alert the user that a target marker has been recognized.
  • the SAW sensor is connected to a computer, wherein any detectable change in frequency can be detected and measured by the computer.
  • an array of SAW sensors (4-6) is used, each coated with a different chemoselective polymer that selectively binds and/or absorbs vapors of specific classes of molecules. The resulting array, or “signature” identifies specific compounds.
  • the sensitivity of a SAW device to record changes in frequency will be reduced.
  • These outer layers of coating material compete for the marker with the layers of coating being sensed and thus reduce the sensitivity of the sensor.
  • Uniformity of the coating is also a critical factor in the performance of a sensor that uses a chemoselective coating since changes in average surface area greatly affect the local vibrational signature of the SAW device. Therefore, films should be deposited that are flat to within 1 nm with a thickness of 15-25 nm. In this regard, it is important not only that the coating be uniform and reproducible from one device to another, so that a set of devices will all operate with the same sensitivity, but also that the coating on a single device be uniform across the active area of the substrate.
  • a coating is non-uniform, the response time to marker exposure and the recovery time after marker exposure are increased and the operating performance of the sensor is impaired.
  • the thin areas of the coating respond more rapidly to a target marker than the thick areas. As a result, the sensor response signal takes longer to reach an equilibrium value, and the results are less accurate than they would be with a uniform coating.
  • PLD pulsed laser deposition
  • COTS Cyrano Sciences, Inc.
  • CSI Cyrano Sciences, Inc.
  • CSI's Portable Electronic Nose and CSI's Nose-Chip integrated circuit for odor-sensing see U.S. Pat. No. 5,945,069— FIG. 1
  • COTS Cyrano Sciences, Inc.
  • CSI's Portable Electronic Nose and CSI's Nose-Chip integrated circuit for odor-sensing see U.S. Pat. No. 5,945,069— FIG. 1
  • These devices offer minimal cycle time, can detect multiple markers, can work in almost any environment without special sample preparation or isolation conditions, and do not require advanced sensor design or cleansing between tests.
  • competitive binding immunoassays can be used to test a bodily fluid sample for the presence of signaling agents.
  • Immunoassay tests generally include an absorbent, fibrous strip having one or more reagents incorporated at specific zones on the strip. The bodily fluid sample is deposited on the strip and by capillary action the sample will migrate along the strip, entering specific reagent zones in which a chemical reaction may take place. At least one reagent is included which manifests a detectable response, for example a color change, in the presence of a minimal amount of a signaling agent of interest.
  • Patents that describe immunoassay technology include the following: U.S. Pat. Nos. 5,262,333 and 5,573,955, both of which are incorporated herein by reference in their entirety.
  • the device of the present invention may be designed so that patients can exhale via the mouth or nose directly onto a sensor of the invention, without needing a breath sampling apparatus.
  • a mouthpiece or nosepiece will be provided for interfacing a patient with the device to readily transmit the exhaled breath to the sensor (See, i.e., U.S. Pat. No. 5,042,501).
  • the output from the neural network is similar when the same patient exhales directly into the device and when the exhaled gases are allowed to dry before the sensor samples them.
  • a patient's breath sample can be captured in a container (vessel) for later analysis using a sensor of the subject invention (i.e., mass spectrometer).
  • a sensor of the subject invention i.e., mass spectrometer
  • the humidity in the exhaled gases represents a problem for certain electronic nose devices (albeit not SAW sensors) that only work with “dry” gases.
  • the present invention may adapt such electronic nose technology so that a patient can exhale directly into the device with a means to dehumidify the samples. This is accomplished by including a commercial dehumidifier or a heat moisture exchanger (HME), a device designed to prevent desiccation of the airway during ventilation with dry gases.
  • HME heat moisture exchanger
  • the patient may exhale through their nose, which is an anatomical, physiological dehumidifier to prevent dehydration during normal respiration.
  • the sensor device can be fitted with a preconcentrator, which has some of the properties of a GC column. The gas sample is routed through the preconcentrator before being passed over the sensor array. By heating and volatilizing the gases, humidity is removed and the marker being measured can be separated from potential interferents.
  • the results from the sensor technology analysis of the bodily fluid samples are optionally provided to the user (or patient) via a reporting means.
  • the sensor technology includes the reporting means.
  • Contemplated reporting means include a computer processor linked to the sensor technology in which electronic or printed results can be provided.
  • the reporting means can include a digital display panel, transportable read/write magnetic media such as computer disks and tapes which can be transported to and read on another machine, and printers such as thermal, laser or ink-jet printers for the production of a printed report.
  • the reporting means can provide the results to the user (or patient) via facsimile, electronic mail, mail or courier service, or any other means of safely and securely sending the report to the patient.
  • Interactive reporting means are also contemplated by the present invention, such as an interactive voice response system, interactive computer-based reporting system, interactive telephone touch-tone system, or other similar system.
  • the report provided to the user (or patient) may take many forms, including a summary of analyses performed over a particular period of time or detailed information regarding a particular bodily fluid sample analysis. Results may also be used to populate a financial database for billing the patient, or for populating a laboratory database or a statistical database.
  • a data monitor/analyzer can compare a pattern of response to previously measured and characterized responses from known markers. The matching of those patterns can be performed using a number of techniques, including neural networks. By comparing the analog output from each of the 32 polymers to a “blank” or control, for example, a neural network can establish a pattern that is unique to that marker and subsequently learns to recognize that marker. The particular resistor geometries are selected to optimize the desired response to the target marker being sensed.
  • the sensor of the subject invention is preferably a self-calibrating polymer system suitable for detecting and quantifying markers in gas phase biological solutions to assess and/or monitor a variety of therapeutic drug markers simultaneously.
  • the senor can include a computer that communicates therewith, which can also notify the medical staff and/or the patient as to any irregularities in dosing, dangerous drug interactions, and the like.
  • This system will enable determination as to whether a patient has been administered a pharmacologically effective amount of a therapeutic drug.
  • the device could also alert the patient (or user) as to time intervals and/or dosage of therapeutic drug to be administered. Accordingly, it is contemplated herein that a sensor of the subject invention can be portable.
  • the senor will be used to identify a baseline spectrum for the patient prior to drug administration, if necessary. This will prove beneficial for the detection of more than one therapeutic drug if the patient receives more than one drug at a time and possible interference from different foods and odors in the stomach, mouth, esophagus and lungs.
  • a further embodiment of the invention includes a communications device in the home (or other remote location) that will be interfaced to the sensor.
  • the home communications device will be able to transmit immediately or at prescribed intervals directly or over a standard telephone line (or other communication transmittal means) the data collected by the data monitor/analyzer device.
  • the communication of the data will allow the user (i.e., physician) to be able to remotely verify if the appropriate dosage of a therapeutic drug is being administered to the patient.
  • the data transmitted from the home can also be downloaded to a computer where the drug blood levels are stored in a database, and any deviations outside of pharmacological efficacy would be automatically flagged (i.e., alarm) so that a user (i.e., patient, physician, nurse) could appropriately adjust the drug dosage per suggestions provided by a computer processing unit connected to the sensor or per dosage suggestions provided by health care personnel (i.e., physician).
  • a user i.e., patient, physician, nurse
  • health care personnel i.e., physician
  • the blood concentration of endogenous compounds can be monitored by utilizing breath sensor technology to detect and/or quantify endogenous compound markers present in exhaled breath. It has been shown that blood and exhaled concentration of certain therapeutic agents (such as propofol) are proportional. However, there has been no indication to date that endogenous compound markers are present in exhaled breath, let alone that the concentration of endogenous compounds in a human's body, specifically in patient blood, are proportional to those present in exhaled breath.
  • certain therapeutic agents such as propofol
  • endogenous compounds and/or their markers are present in exhaled breath and can be detected using the sensor technology described herein.
  • endogenous compounds that are hydrophilic are likely to be measured in the liquid (exhaled breath condensate) phase of breath whereas those that are hydrophobic (lipophilic) are likely to be measured in the gas phase of breath.
  • certain endogenous compounds, such as glucose to be present in exhaled breath and that the concentration of the endogenous compounds in exhaled breath is proportional to the concentration in patient blood.
  • a researcher ingested a 100 gm glucose solution and sampled breath and blood glucose levels 40 and 20 minutes before ingestion and multiple times for 120 minutes after ingestion.
  • Glucose was readily detectable in the exhaled breath, which was condensed into a liquid. The concentration of both the breath and blood glucose rose and fell at the same rates. Correlation would be even tighter if only end-tidal breath samples were collected.
  • the systems and methods of the invention may be used to monitor such endogenous compounds as, but not limited to, glucose; proteins (e.g., heat shock proteins HSP70); urobilinogen; urobilirubin; bilirubin; hormones including cortisol, testosterone, estrogens, and pregnancy markers (e.g., hCG and its subunits); oligonucleotides (e.g., DNA, RNA); adenosine; adenosine triphosphate (ATP); adenosine diphosphate (ADP); adenosine monophosphate (AMP); prostaglandins (e.g., PGF2 ⁇ ); leukotrienes; cytokines; interleukins; melatonin; 6-sulfoxymelatonin; hypoxia-inducible factor 1 ⁇ (HIF-1 ⁇ ); myogenic regulatory factors; 2,3-diphosphoglycerate (2,3-DPG); ketones; nitrite; electrolytes (e
  • the present invention provides the capability of non-invasively, and in certain instances continuously, measuring a wide variety of endogenous compound concentrations in blood using exhaled breath as a surrogate, providing a physician with the ability to monitor and diagnose a variety of ailments, such as renal, hepatic, pancreatic, gastrointestinal, and cardiovascular problems via breath collection.
  • a system of the invention comprises a sensor device, a computing/processor device, a system controller, and a controlled supply means for automated delivery of a therapeutic drug.
  • the sensor device preferably detects endogenous compound marker concentration in breath and is connected to communicate the results to the computing/processor device.
  • the computing/processor device runs under control of a program stored in the memory of the computing/processor device and determines a desired therapeutic drug and/or dosage of a therapeutic drug in response to the results provided by the sensor.
  • the computing/processor device comprises a data monitor/analyzer that can compare a pattern of results communicated from the sensor device to previously measured and characterized results, where the results are indicative of patient condition.
  • the computing/processor device preferably utilizes a trainable neural network to determine the therapeutic drug and/o therapeutic drug dosage to be administered to the patient based on the patient's condition and generates a response signal.
  • the system controller responsive to the response signal of the computing/processor device, directs the controlled supply means to dispense a dosage or adjust a dosage for a therapeutic drug.
  • the concentration of the endogenous compound in blood can be determined by the computing/processor device for use in establishing clinically relevant data regarding the patient's condition and, when appropriate, deriving the appropriate type of therapeutic drug and dosage amount to be delivered to the patient to address the patient's condition. In certain embodiments, such information regarding appropriate drug and dosage is communicated to the user.
  • an automated system for monitoring the concentration of glucose present in breath, where the concentration of glucose is indicative of blood glucose concentration, which can be used to derive diabetic patient condition.
  • patient exhaled breath is applied to a sensor (such as an electronic nose), which continuously or intermittently communicates results to a computing/processor device to derive the concentration of glucose present in breath (and corresponding level of glucose in blood).
  • the computing/processor device Based on the monitored glucose concentration in breath, the computing/processor device communicates with the system controller of the invention, which will direct the controlled supply means (e.g., IV bag) to dispense (or refrain from dispensing) an appropriate dosage of a therapeutic drug, such as insulin, to address the patient's condition.
  • the system of the invention can automatically deliver insulin to the patient to lower blood glucose levels.
  • drug affinity i.e., degree of attraction between a drug and a target receptor in the patient body
  • drug distribution i.e., binding of drug to proteins circulating in the blood, absorption of drug into fat
  • drug metabolism and elimination i.e., renal clearance
  • existence of a drug in a “free” form may affect drug pharmacodynamics and pharmacokinetics (PD/PK) in a patient.
  • PD/PK drug pharmacodynamics and pharmacokinetics
  • a drug bound to protein or absorbed into fat does not produce a desired pharmacological effect and exists in equilibrium with unbound drug. Numerous factors, including competition for binding sites on the protein from other drugs, the amount of fat in the body, and the amount of protein produced, determine the equilibrium between bound and unbound drug.
  • An unbound drug can participate directly in the pharmacological effect or be metabolized into a drug that produces a desired effect. Metabolism of the active drug often leads to its removal from the bloodstream and termination of its effect. The drug effect can also be terminated by the excretion of the free drug. Free drug or a metabolite can be excreted in the urine or the digestive tract or in exhaled breath. The concentration in the blood (or plasma or serum) of such therapeutic drugs is related to the clinical effect of the agent.
  • blood concentration testing for a therapeutic drug may or may not provide an accurate indication of the effect of the therapeutic drug on a patient, since measurement of blood concentration does not account for the quantity of drug bound to protein or membranes, or the interaction and competition between drugs. For this reason, it would be advantageous to measure only the free drug in the plasma.
  • the concentration of free drug in plasma is usually low and requires sophisticated and expensive analytical techniques for measurement.
  • the marker that appears in breath in accordance with the subject invention, is an indication of the concentration of free drug in blood.
  • using the systems and methods of the subject invention to measure exhaled breath for marker concentration can provide an effective indicator of the actual concentration of free drug responsible for PK effect.
  • testing blood directly is invasive, time consuming, expensive, and prone to inaccuracies.
  • the systems and methods of the subject invention are non-invasive, speedy, and accurate and can be performed intermittently or continuously.
  • a therapeutic drug marker such as the therapeutic drug or its metabolite
  • the concentration in expired breath is proportional to the free therapeutic drug (or metabolite) concentration in the blood and, thus, indicative of the rate of drug absorption, distribution, metabolism, and/or elimination.
  • the metabolite measured in exhaled breath maybe the active metabolite or a breakdown product of the active therapeutic drug.
  • the activity of the active drug can be analyzed in accordance with the subject invention.
  • the method of the present invention takes into account such proportional concentrations and allows for the determination of the rate of absorption, distribution, metabolism, and elimination of a therapeutic drug by measuring concentration of unbound substances, markers, and/or active metabolites associated with the drug in a patient's breath. The proper dosing regimen can thus be determined therefrom.
  • therapeutic drug markers useful as an indication of therapeutic drug concentration in blood include the following olfactory markers, without limitation: dimethyl sulfoxide (DMSO), acetaldehyde, acetophenone, trans-Anethole (1-methoxy-4-propenyl benzene) (anise), benzaldehyde (benzoic aldehyde), benzyl alcohol, benzyl cinnamate, cadinene, camphene, camphor, cinnamaldehyde (3-phenylpropenal), garlic, citronellal, cresol, cyclohexane, eucalyptol, and eugenol, eugenyl methyl ether; butyl isobutyrate (n-butyl 2, methyl propanoate) (pineapple); citral (2-trans-3,7-dimethyl-2,6-actadiene-1-al); menthol (1-methyl-4-is
  • markers are preferred since they are used in the food industry as flavor ingredients and are permitted by the Food and Drug Administration.
  • olfactory markers for use in the present invention can be selected from a vast number of available compounds (see Fenaroli's Handbook of Flavor Ingredients, 4 th edition, CRC Press, 2001) and use of such other applicable markers is contemplated herein.
  • the markers of the invention also include additives that have been federally approved and categorized as GRAS (“generally recognized as safe”), which are available on a database maintained by the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition.
  • Markers categorized as GRAS that are readily detectable in exhaled breath include, but are not limited to, sodium bisulfate, dioctyl sodium sulfosuccinate, polyglycerol polyricinoleic acid, calcium casein peptone-calcium phosphate, botanicals (i.e., chrysanthemum; licorice; jellywort, honeysuckle; lophatherum, mulberry leaf; frangipani; self heal; sophora flower bud), ferrous bisglycinate chelate, seaweed-derived calcium, DHASCO (docosahexaenoic acid-rich single-cell oil) and ARASCO (arachidonic acid-rich single-cell oil), fructooligosaccharide, tre
  • Halogenated compounds i.e. fluorinated drugs or markers
  • Some of these compounds are used as propellants for delivery of drugs via the pulmonary route, such as metered dose inhalers and therefore are known to be safe and are FDA approved, some are GRAS compounds as well.
  • the technologies most often used to detect Freon leaks include: Negative Ion Capture, Heated Sensor/Ceramic Semiconductor, Infrared Absorption, and TIF TIFXP-1A Negative Corona Leak Detector.
  • Many drugs are fluorinated and metabolites are often extremely volatile and detectable in exhaled breath. Numerous such compounds are available that could be used as markers and could be added as excipients during the manufacture of drugs.
  • therapeutic drug markers are detected by their physical and/or chemical properties, which does not preclude using the desired therapeutic drug itself as its own marker.
  • Therapeutic drug markers also include products and compounds that are administered to enhance detection using sensors of the invention.
  • therapeutic drug markers can include a variety of products or compounds that are added to a desired therapeutic drug regimen to enhance differentiation in detection/quantification.
  • therapeutic drug markers are poorly soluble in water, which enhances their volatility and detection in the breath.
  • the detection of the marker can occur under several circumstances.
  • the marker can “coat” or persist in the mouth, esophagus and/or stomach upon ingestion and be detected with exhalation (similar to the taste or flavor that remains in the mouth after eating a breath mint).
  • the drug in a second instance where the drug (and, when present, detectable additive) is administered orally, the drug may react in the mouth or stomach with acid or enzymes to produce or liberate the marker that can then be detected upon exhalation.
  • the drug and/or marker can be absorbed in the gastrointestinal tract and be excreted in the lungs (i.e. alcohol is rapidly absorbed and detected with a Breathalyzer).
  • a therapeutic drug marker of the invention provides a means for determining the pharmacodynamics and pharmacokinetics of the drug.
  • a detectable additive is concurrently administered with a therapeutic drug (i.e., detectable additive is provided in a pharmaceutically acceptable carrier, detectable additive is provided in medication coating composed of rapidly dissolving glucose and/or sucrose).
  • the therapeutic drug is provided in the form of a pill, whose coating includes at least one marker in air-flocculated sugar crystals. This would stimulate salivation and serve to spread the marker around the oral cavity, enhancing the lifetime in the cavity. Since the throat and esophagus could also be coated with the marker as the medication is ingested, detection of the marker is further enhanced.
  • the preferred embodiment of the invention detects and quantifies a therapeutic drug marker almost immediately in the exhaled breath of the patient (or possibly by requesting the patient to deliberately produce a burp) using a sensor (i.e., electronic nose).
  • a sensor i.e., electronic nose.
  • Certain drug compositions might not be detectable in the exhaled breath. Others might have a coating to prevent the medication from dissolving in the stomach.
  • a non-toxic olfactory marker i.e., volatile organic vapors
  • the pharmaceutically acceptable carrier i.e., the coating of a pill, in a separate fast dissolving compartment in the pill, or solution, if the drug is administered in liquid or suspension form
  • the pharmaceutically acceptable carrier i.e., the coating of a pill, in a separate fast dissolving compartment in the pill, or solution, if the drug is administered in liquid or suspension form
  • the marker will coat the oral cavity or esophagus or stomach for a short while and be exhaled in the breath (or in a burp).
  • the markers can be applied as coatings or physically combined or added to therapeutic drug. Markers can also be included with therapeutic drugs that are administered in liquid form (i.e., syrups, via inhalers, or other dosing means).
  • the therapeutic drug markers of the invention could be used for indicating specific drugs or for a class of drugs.
  • a patient may be taking an anti-depressant (tricyclics such as nortriptyline), antibiotic, an antihypertensive agent (i.e., clonidine), pain medication, and an anti-reflux drug.
  • an anti-depressant tricyclics such as nortriptyline
  • antibiotic an antihypertensive agent
  • clonidine antihypertensive agent
  • pain medication i.e., clonidine
  • an anti-reflux drug i.e., clonidine
  • One marker could be used for antibiotics as a class, or for subclasses of antibiotics, such as erythromycins.
  • Another marker could be used for antihypertensives as a class, or for specific subclasses of antihypertensives, such as calcium channel blockers. The same would be true for the anti-reflux drug.
  • combinations of marker substances could
  • therapeutic drugs to be monitored in accordance with the subject invention include, but are not limited to, anesthetic agents, psychiatric drugs (i.e., antidepressants, anti-psychotics, anti-anxiety drugs, depressants), analgesics, stimulants, biological response modifiers, NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs), anabolic steroids, antacids, antiarrhythmics, antibacterials, antibiotics, anticoagulants and thrombolytics, anticonvulsants, antidiarrheals, antiemetics, antihistamines, antihypertensives, anti-inflammatories, antineoplastics, antipyretics, antivirals, barbiturates, ⁇ -blockers, bronchodilators, cough suppressants, cytotoxics, decongestants, diuretics, expectorants, hormones, immunosuppressives, hypoglycemics, laxatives
  • the subject invention can effectively monitor concentrations of the following non-limiting list of therapeutic drugs in blood: drugs for the treatment of rheumatoid arthritis or symptoms thereof, systemic lupus erythematosus or symptoms thereof, degenerative arthritis, vasculitis, inflammatory diseases, angina, coronary artery disease, peripheral vascular disease; ulcerative colitis, and Crohn's disease; anti organ rejection drugs; antiepilepsy medication; and anti-anxiety drugs.
  • Therapeutic drugs whose concentration levels in blood can be monitored in accordance with the subject invention include, but are not limited to, the following: ⁇ -Hydroxy-Alprazolam; Acecainide (NAPA); Acetaminophen (Tylenol); Acetylmorphine; Acetylsalicylic Acid (as Salicylates); ⁇ -hydroxy-alprazolam; Alprazolam (Xanax); Amantadine (Symmetrel); Ambien (Zolpidem); Amikacin (Amikin); Amiodarone (Cordarone); Amitriptyline (Elavil) & Nortriptyline; Amobarbital (Amytal); Anafranil (Clomipramine) & Desmethyldlomipramine; Ativan (Lorazepam); Aventyl (Nortriptyline); Benadryl (Dephenhydramine); Benziodiazepines; Benzoylecgonine; Benztropine (Cogent
  • Additional therapeutic drugs whose blood concentration levels can be monitored in accordance with the subject invention include Celontin (Methsuximide) (as desmethylmethsuximide); Centrax (Prazepam) (as Desmethyldiazepam); Chloramphenicol (Chloromycetin); Chlordiazepoxide; Chlorpromazine (Thorazine); Chlorpropamide (Diabinese); Clonazepam (Klonopin); Clorazepate (Tranxene); Clozapine; Cocaethylene; Codeine; Cogentin (Benztropine); Conipazine (Prochlorperazine); Cordarone (Amiodarone); Coumadin (Warfarin); Cyclobenzaprine (Flexeril); Cyclosporine (Sandinmmune); Cylert (Pemoline); Dalmane (Flurazepam) & Desalkylflurazepam; Daivocet; Darvon (Propoxyphene
  • Blood level concentrations of the following therapeutic drugs that can be monitored in accordance with the subject invention include, but are not limited to, Maprotiline; Mebaral (Mephobarbital) & Phenobarbital; Mellaril (Thioridazine) & Mesoridazine; Mephenytoin (Mesantoin); Meprobamate (Miltown, Equanil); Mesantoin (Mephenyto:in); Mesoridazine (Serentil); Methadone; Methotrexate (Mexate); Methsuximide (Celontin) (as desmethsuximide); Mexiletine (Mexitil); Midazolam (Versed); Mirtazapine (Remeron); Mogadone (Nitrazepam); Molindone (:Moban); Morphine; Mysoline (Primidone) & Phlenobarbital; NAPA & Procainamide (Pronestyl); NAPA (
  • Therapeutic drugs of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.
  • Formulations are described in a number of sources, which are well known and readily available to those skilled in the art.
  • Remington 's Pharmaceutical Science (Martin E W [1995] Easton Pennsylvania, Mack Publishing Company, 19 th ed.) describes formulations that can be used in connection with the subject invention.
  • Formulations suitable for parenteral administration include, for example, aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes, which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions, which may include suspending agents and thickening agents.
  • Formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use.
  • sterile liquid carrier for example, water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the subject invention can include other agents conventional in the art having regard to the type of formulation in question.
  • a therapeutic drug in accordance with the subject invention, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art.
  • a therapeutic drug is formulated in a patentable and easily consumed oral formulation such as a pill, lozenge, tablet, gum, beverage, etc.
  • a therapeutic drug can be delivered from a controlled supply means (i.e., pill dispenser, IV bag, etc.).
  • a sensor of the invention analyzes a patient's expired gases to detect at least one target marker of the therapeutic drug.
  • the concentration of the therapeutic drug in blood can be determined for use in deriving the appropriate dosage amount of the therapeutic drug to next be delivered to the patient.
  • a system controller utilizes the derived appropriate dosage based on exhaled breath analysis to dispense an appropriate dosage from the supply means to the patient.
  • Pulmonary delivery of medications is well known, especially for conditions such as asthma and chronic obstructive pulmonary disease.
  • medication i.e. corticosteroids, bronchodilators, anticholinergics, etc.
  • medication i.e. corticosteroids, bronchodilators, anticholinergics, etc.
  • MDIs Metered dose inhalers
  • nebulizers are commonly used to deliver medication by this route.
  • dry powder inhalers have become increasingly popular, as they do not require the use of propellants such as CFCs. Propellants have been implicated in worsening asthma attacks, as well as depleting the ozone layer. Dry power inhalers are also being used for drugs that were previously given only by other routes, such as insulin, peptides, and hormones.
  • Olfactory markers can be added to these delivery systems as well. Since the devices are designed to deliver medication by the pulmonary route, the sensor array can be incorporated into the device and the patient need only exhale back through the device for documentation to occur.
  • anesthetic agents are administered directly into a patient's bloodstream rather than administering gases through a breathing circuit.
  • the administered drug may bind to proteins circulating in the blood, be absorbed into fat or exist in a “free” form. Drug bound to protein or absorbed in fat does not produce a pharmacological effect and exists in equilibrium with unbound drug. Numerous factors, including competition for binding sites on the protein from other drugs, the amount of fat in the body and the amount of protein produced, determine the equilibrium between bound and unbound drug. Unbound drug may participate directly in the pharmacological effect or be metabolized into a drug that produces the effect. Metabolism of the active drug often leads to its removal from the bloodstream and termination of its effect.
  • the drug effect can also be terminated by the excretion of the free drug.
  • Free drug or a metabolite can be excreted in the urine or the digestive tract or in exhaled breath.
  • the concentration in the blood (or plasma or serum) of such agents e.g., propofol, alfentanil and remifentanil
  • concentration in the blood (or plasma or serum) of such agents is related to the clinical effect of the agent.
  • FIG. 3 represents the FT-IR signal for propofol (2,6-diisopropylphenol). It has been specifically shown that there is a good correlation between blood concentration of anesthetic agents (e.g., propofol) and depth of anesthesia. Therefore, testing blood concentration is a good indicator of the effect of the agent (depth of anesthesia). Unfortunately, testing blood directly is invasive and time consuming. When a drug or its metabolite is excreted in the breath, the concentration in expired breath is proportional to the free drug or metabolite concentration in the blood and, thus, indicative of depth of anesthesia and/or the rate of drug metabolism. The metabolite measured in exhaled breath may be the active metabolite or a breakdown product of the active drug.
  • anesthetic agents e.g., propofol
  • the method of the present invention takes into account such proportional concentrations and allows for the determination of depth of anesthesia and/or the rate of metabolism of the drug by measuring concentration of unbound substances, agents and/or active metabolites in a patient's breath, see FIG. 4 .
  • the proper dosing regimen can thus be determined therefrom.
  • the exhalation gas stream comprises sequences or stages. At the beginning of exhalation there is an initial stage, the gas representative thereof coming from an anatomically inactive (deadspace) part of the respiratory system, in other words, from the mouth and upper respiratory tracts. This is followed by a plateau stage. Early in the plateau stage, the gas is a mixture of deadspace and metabolically active gases. The last portion of the exhaled breath comprises nothing but deep lung, so-called alveolar gas. This gas, which comes from the alveoli, is termed end-tidal gas. In one embodiment, the exhaled breath sample is collected at end-tidal breathing. Technology similar to that used for end-tidal carbon dioxide monitoring can be used to determine when the sample is collected.
  • Airway pressure measurements afford another means of collecting samples at the appropriate phase of the respiratory cycle.
  • Single or multiple samples collected by the side stream method are preferable, but if sensor acquisition time is reduced, in-line sampling may be used.
  • samples are collected through an adapter at the proximal end of the endotracheal tube and drawn through thin bore tubing to the sensor chamber.
  • gas may be collected on successive cycles.
  • the sensor is placed proximal to the ET tube directly in the gas stream.
  • samples can be taken throughout the exhalation phase of respiration and average value determined and correlated with blood concentration.
  • FIG. 5 a the characteristic signature of propofol from a four (4) sensor polymer coated SAW array is shown.
  • 1 cc of propofol was placed in a “headspace” gas chromatography vial.
  • a 19-gauge hypodermic needle attached to a VaporLabTM gas detector containing the sensor array was inserted into the vial, which was heated to 37° C., and the “signature” was recorded.
  • the VaporLabTM brand instrument is a hand-held, battery powered SAW based chemical vapor identification instrument suitable for detecting vapors in accordance with the present invention.
  • This instrument is sensitive to volatile and semi-volatile compounds and has a high-stability SAW sensor array that provides orthogonal vapor responses for greater accuracy and discrimination.
  • the device communicates with computers to provide enhanced pattern analysis and report generation.
  • the device can be easily “trained” to remember chemical vapor signature patterns for fast, “on-the-fly” analysis. Note that the “signature” has both amplitude and temporal resolution.
  • vapor concentration measurements of vapors are made by detecting the adsorption of molecules onto the surface of a SAW sensor coated with a polymer thin film. This thin film is specifically coated to provide selectivity and sensitivity to specific vapors.
  • the SAW is inserted as an active feedback element in an oscillator circuit.
  • a frequency counter measures the oscillation frequency, which corresponds to the resonant frequency of the SAW sensor.
  • the response of the SAW sensor to the vapor is measured as a shift in the resonant frequency of the SAW sensor.
  • This configuration requires an oscillator circuit, the coated SAW sensor, and a frequency counter, all of which can be housed on a small printed circuit board.
  • FIG. 5 b shows an example of a Propofol relative breath concentration profile in a patient.
  • samples are collected at the distal end of the endotracheal tube (ETT) through a tube with a separate sampling port. This may improve sampling by allowing a larger sample during each respiratory cycle.
  • ETT endotracheal tube
  • the concentration of an anesthetic agent in the body is regulated both by the amount of the agent administered over a given time period and the rate at which the agent is eliminated from the body (metabolism).
  • the present invention provides the steps of administering an agent to the subject and analyzing exhaled breath of the subject for concentration of unbound substances, active metabolites, or inactive metabolites after a suitable time period; the concentration indicates a characteristic of metabolism of the agent in the subject.
  • the method may further include using a flow sensor to detect starting and completion of exhalation.
  • the method further includes providing results from the analysis and controlling the infusion pump for delivering the intravenous anesthesia agent based on the results.
  • a CPU may be provided as a data processing/control unit for automatically detecting the signal from the flow sensor to control sampling of exhaled breath.
  • the CPU may further provide the analysis and control of the infusion pump or other administering means.
  • an infusion pump may be used.
  • Compounds may be also administered parenterally, sublingually, transdermally, by i.v. bolus, and by continuous infusion.
  • a number of suitable agents are available for administration as also known by those skilled in the art (Remifentanil—Glaxo Wellcome, Propofol—Zeneca).
  • Agents may also be those of amnesia, analgesia, muscle relaxation, and sedation agents or a combination thereof.
  • Agents may be administered in an amount for analgesia, conscious sedation, or unconsciousness as known in the art. Patient characteristics may also be monitored during administration of the agent.
  • Concentration in the blood as measured by the breath analysis of the present invention for free agents or metabolites may indicate when the patient is receiving an anesthetic concentration (a high dose), an analgesic concentration (a low dose), or emerging from anesthesia as a result of a level that allows for full recovery. Even if there is wide variation in the metabolism or response to an anesthetic agent, knowledge of the exhaled breath concentration allows the anesthesiologist to know if the drug is accumulating in the blood, possibly leading to a dangerously deep level of anesthesia and/or a prolonged recovery time: or, the concentration is falling, possibly leading to inadequate anesthesia and premature emergence. Monitoring changes in concentration are, therefore, useful.
  • the exhalation air is measured for free agent and/or metabolite concentration either continuously or periodically. From the exhalation air is extracted at least one measured free agent or metabolite concentration value.
  • the apparatus includes a conventional flow channel through which exhalation air flows. The flow channel is provided with sensor elements for measuring free agent or metabolite concentration.
  • the apparatus includes necessary output elements for delivering at least a measured concentration result to the operator, if necessary. An alarm mechanism may also be provided.
  • An instrument of similar type is shown in FIGS. 1 and 2 of U.S. Pat. No. 5,971,937 incorporated herein by reference.
  • the device of the present invention may be designed so that patients can exhale via the mouth or nose directly into the device, FIG. 4 .
  • the senor will be used to identify a baseline spectrum for the patient prior to delivery, if necessary. This will prove beneficial for the detection of more than one drug if the patient receives more than one drug at a time and possible interference from different foods and odors in the stomach, mouth, esophagus and lungs.
  • a breathing system is an assembly of components which connects the patient's airway to the anesthetic machine, from and into which the patient breathes.
  • such systems generally include a fresh gas entry port/delivery tube through which the gases are delivered from the machine; a port to connect it to the patient's airway (oral airway, mask, endotracheal tube); a reservoir for gas; a expiratory port/valve through which the expired gas is vented to the atmosphere; a carbon dioxide absorber (for rebreathing); and tubes for connecting these components.
  • Flow directing valves may or may not be used.
  • the sensors of the present invention are in communication with the delivered (inspired) gas and/or the expired gas of the breathing circuit to appropriately monitor the target substance(s).
  • the sensors are in flow communication with the appropriate tubes, valves, etc. of the circuit.
  • FIGS. 6 a and 6 b show the unique signatures of the inhalational anesthetics Isoflurane and Sevoflurane, respectively, sampled from a breathing circuit. Sensors may be placed throughout the breathing circuit to obtain readings for target substances.
  • inspired gases are monitored by connecting the sensor(s) of the present invention to the appropriate location(s) in the breathing circuit.
  • expired gases are monitored by connecting the sensor(s) of the present invention to the appropriate location(s) in the breathing circuit.
  • samples are collected at the distal end of the endotracheal tube (ETT) through a tube with a separate sampling port. This may improve sampling by allowing a larger sample during each respiratory cycle.
  • Monitored expired gases include, for example, physiologic gases and anesthetic gases. If IV anesthesia is also administered, as in “balanced anesthesia,” monitoring expired gases will also include measuring concentration in the blood by the breath analysis of the present invention.
  • side-stream monitoring is used.
  • a water trap, desiccant and/or filter may be used to remove water vapor and condensation from the sample.
  • the device of the present invention continuously samples and measures inspired and exhaled (end-tidal) concentrations of respiratory gases.
  • the monitored gases are both the physiologic gases found in the exhaled breath of patients (oxygen, carbon dioxide, and nitrogen), as well as those administered to the patient by the anesthesiologist in order to induce and maintain analgesia and anesthesia.
  • the sensors of the present invention may also monitor purity of gases at the entry port (fresh gas entry) and/or carrier gases. If multiple volatile anesthetic agents are connected to the circuit, an appropriate number of sensors may be included to detect each of such agents at the respective entry points as well as prior to inspiration.
  • any number of sensors may be used at various points in the circuit to accomplish the desired monitoring. All of the sensors may connect to a single processor for analysis or use multiple processors. Similarly, the results of the monitoring may be displayed through a single display device or multiple display devices as desired.
  • the method and apparatus of the present invention will detect and quantitate the concentration of the target substances.
  • Microgravimetric sensors are based on the preparation of polymeric- or biomolecule-based sorbents that are selectively predetermined for a particular substance, or group of structural analogs.
  • a direct measurement of mass changes induced by binding of a sorbent with a target marker can be observed by the propagation of acoustic shear waves in the substrate of the sensor.
  • Phase and velocity of the acoustic wave are influenced by the specific adsorption of target markers onto the sensor surface.
  • Piezoelectric materials such as quartz (SiO 2 ) or zinc oxide (ZnO), resonate mechanically at a specific ultrasonic frequency when excited in an oscillating field.
  • Electromagnetic energy is converted into acoustic energy, whereby piezoelectricity is associated with the electrical polarization of materials with anisotropic crystal structure.
  • the oscillation method is used to monitor acoustic wave operation. Specifically, the oscillation method measures the series resonant frequency of the resonating sensor.
  • Types of sensors derived from microgravimetric sensors include quartz crystal microbalance (QCM) devices that apply a thickness-shear mode (TSM) and devices that apply surface acoustic wave (SAW) detection principle.
  • Additional devices derived from microgravimetric sensors include the flexural plate wave (FPW), the shear horizontal acoustic plate (SH-APM), the surface transverse wave (STW) and the thin-rod acoustic wave (TRAW).
  • Conducting polymer sensors promise fast response time, low cost, and good sensitivity and selectivity.
  • the technology is relatively simple in concept.
  • a conductive material such as carbon
  • a conductive material is homogeneously blended in a specific non-conducting polymer and deposited as a thin film on an aluminum oxide substrate.
  • the films lie across two electrical leads, creating a chemoresistor.
  • As the polymer is subjected to various chemical vapors, it expands, increasing the distance between carbon particles, and thereby increasing the resistance.
  • the polymer matrix swells because analyte vapor absorbs into the film to an extent determined by the partition coefficient of the analyte.
  • the partition coefficient defines the equilibrium distribution of an analyte between the vapor phase and the condensed phase at a specified temperature.
  • Each individual detector element requires a minimum absorbed amount of analyte to cause a response noticeable above the baseline noise.
  • Selectivity to different vapors is accomplished by changing the chemical composition of the polymer. This allows each sensor to be tailored to specific chemical vapors. Therefore, for most applications an array of orthogonal responding sensors is required to improve selectivity. Regardless of the number of sensors in the array, the information from them must be processed with pattern recognition software to correctly identify the chemical vapors of interest. Sensitivity concentrations are reportedly good (tens of ppm). The technology is very portable (small and low power consumption), relatively fast in response time (less than 1 minute), low cost, and should be rugged and reliable.
  • Electrochemical sensors measure a change in output voltage of a sensing element caused by chemical interaction of a target marker on the sensing element.
  • Certain electrochemical sensors are based on a transducer principle. For example, certain electrochemical sensors use ion-selective electrodes that include ion-selective membranes, which generate a charge separation between the sample and the sensor surface. Other electrochemical sensors use an electrode by itself as the surface as the complexation agent, where a change in the electrode potential relates to the concentration of the target marker. Further examples of electrochemical sensors are based on semiconductor technology for monitoring charges at the surface of an electrode that has been built up on a metal gate between the so-called source and drain electrodes. The surface potential varies with the target marker concentration.
  • Additional electrochemical sensor devices include amperometric, conductometric, and capacitive immunosensors.
  • Amperometric immunosensors are designed to measure a current flow generated by an electrochemical reaction at a constant voltage.
  • electrochemically active labels directly, or as products of an enzymatic reaction, are needed for an electrochemical reaction of a target marker at a sensing electrode.
  • Any number of commonly available electrodes can be used in amperometric immunosensors, including oxygen and H 2 O 2 electrodes.
  • Capacitive immunosensors are sensor-based transducers that measure the alteration of the electrical conductivity in a solution at a constant voltage, where alterations in conductivity are caused by biochemical enzymatic reactions, which specifically generate or consume ions. Capacitance changes are measured using an electrochemical system, in which a bioactive element is immobilized onto a pair of metal electrodes, such as gold or platinum electrodes.
  • Conductometric immunosensors are also sensor-based transducers that measure alteration of surface conductivity. As with capacitive immunosensors, bioactive elements are immobilized on the surface of electrodes. When the bioactive element interacts with a target marker, it causes a decrease in the conductivity between the electrodes.
  • Electrochemical sensors are excellent for detecting low parts-per-million concentrations. They are also rugged, draw little power, linear and do not require significant support electronics or vapor handling (pumps, valves, etc.) They are moderate in cost ($50 to $200 in low volumes) and small in size.
  • Gas Chromatography/Mass Spectrometry is actually a combination of two technologies.
  • One technology separates the chemical components (GC) while the other one detects them (MS).
  • gas chromatography is the physical separation of two or more compounds based on their differential distribution between two phases, the mobile phase and stationary phase.
  • the mobile phase is a carrier gas that moves a vaporized sample through a column coated with a stationary phase where separation takes place.
  • a detector converts the column eluent to an electrical signal that is measured and recorded. The signal is recorded as a peak in the chromatogram plot. Chromatograph peaks can be identified from their corresponding retention times.
  • the retention time is measured from the time of sample injection to the time of the peak maximum, and is unaffected by the presence of other sample components. Retention times can range from seconds to hours, depending on the column selected and the component.
  • the height of the peak relates to the concentration of a component in the sample mixture.
  • Mass spectrometry is one such detection method, which bombards the separated sample component molecules with an electron beam as they elute from the column. This causes the molecules to lose an electron and form ions with a positive charge. Some of the bonds holding the molecule together are broken in the process, and the resulting fragments may rearrange or break up further to form more stable fragments. A given compound will ionize, fragment, and rearrange reproducibly under a given set of conditions. This makes identification of the molecules possible.
  • a mass spectrum is a plot showing the mass/charge ratio versus abundance data for ions from the sample molecule and its fragments. This ratio is normally equal to the mass for that fragment. The largest peak in the spectrum is the base peak.
  • the GC/MS is accurate, selective and sensitive.
  • Infrared (IR) spectroscopy is one of the most common spectroscopic techniques used by organic and inorganic chemists. Simply, it is the absorption measurement of different IR frequencies by a sample positioned in the path of an IR beam. IR radiation spans a wide section of the electromagnetic spectrum having wavelengths from 0.78 to 1000 micrometers (microns). Generally, IR absorption is represented by its wave number, which is the inverse of its wavelength times 10,000. For a given sample to be detected using IR spectroscopy, the sample molecule must be active in the IR region, meaning that the molecule must vibrate when exposed to IR radiation. Several reference books are available which contain this data, including the Handbook of Chemistry and Physics from the CRC Press.
  • IR spectrometers There are two general classes of IR spectrometers—dispersive and non-dispersive.
  • a typical dispersive IR spectrometer radiation from a broadband source passes through the sample and is dispersed by a monochromator into component frequencies. The beams then fall on a detector, typically a thermal or photon detector, which generates an electrical signal for analysis.
  • Fourier Transform IR spectrometers FTIR
  • FTIR Fourier Transform IR spectrometers
  • the NDIR non-dispersive IR
  • the NDIR instead of sourcing a broad IR spectrum for analyzing a range of sample gases, the NDIR sources a specific wavelength which corresponds to the absorption wavelength of the target sample. This is accomplished by utilizing a relatively broad IR source and using spectral filters to restrict the emission to the wavelength of interest.
  • NDIR is frequently used to measure carbon monoxide (CO), which absorbs IR energy at a wavelength of 4.67 microns.
  • CO carbon monoxide
  • NDIR sensors promise low cost (less than $200), no recurring costs, good sensitivity and selectivity, no calibration and high reliability. They are small, draw little power and respond quickly (less than 1 minute). Warm up time is nominal (less than 5 minutes). Unfortunately, they only detect one target gas. To detect more gases additional spectral filters and detectors are required, as well as additional optics to direct the broadband IR source.
  • IMS Ion Mobility Spectrometry
  • IMS Ion Mobility Spectrometry
  • IMS is an extremely fast method and allows near real time analysis. It is also very sensitive, and should be able to measure all the analytes of interest. IMS is moderate in cost (several thousand dollars) and larger in size and power consumption.
  • MOS Metal Oxide Semiconductor
  • Metal Oxide Semiconductor (MOS) sensors utilize a semiconducting metal-oxide crystal, typically tin-oxide, as the sensing material.
  • the metal-oxide crystal is heated to approximately 400° C., at which point the surface adsorbs oxygen. Donor electrons in the crystal transfer to the adsorbed oxygen, leaving a positive charge in the space charge region. Thus, a surface potential is formed, which increases the sensor's resistance. Exposing the sensor to deoxidizing, or reducing, gases removes the surface potential, which lowers the resistance. The end result is a sensor which changes its electrical resistance with exposure to deoxidizing gases. The change in resistance is approximately logarithmic.
  • MOS sensors have the advantage of being extremely low cost (less than $8 in low volume) with a fast analysis time (milliseconds to seconds). They have long operating lifetimes (greater than five years) with no reported shelf life issues.
  • TMS Thickness-Shear Mode Sensors
  • TSM sensors consist of an AT-cut piezoelectric crystal disc, most commonly of quartz because of its chemical stability in biological fluids and resistance to extreme temperatures, and two electrodes (preferably metal) attached to opposite sides of the disc. The electrodes apply the oscillating electric field.
  • TSM sensor devices are run in a range of 5-20 MHz. Advantages are, besides the chemical inertness, the low cost of the devices and the reliable quality of the mass-produced quartz discs.
  • Photo-Ionization Detectors rely on the fact that all elements and chemicals can be ionized.
  • the energy required to displace an electron and ‘ionize’ a gas is called its Ionization Potential (IP), measured in electron volts (eV).
  • IP Ionization Potential
  • a PID uses an ultraviolet (UV) light source to ionize the gas.
  • UV light source must be at least as great as the IP of the sample gas.
  • benzene has an IP of 9.24 eV
  • carbon monoxide has an IP of 14.01 eV.
  • the UV lamp must have at least 9.24 eV of energy.
  • both the benzene and the carbon monoxide would be ionized. Once ionized, the detector measures the charge and converts the signal information into a displayed concentration. Unfortunately, the display does not differentiate between the two gases, and simply reads the total concentration of both summed together.
  • UV lamp energies are commonly available: 9.8, 10.6 and 11.7 eV. Some selectivity can be achieved by selecting the lowest energy lamp while still having enough energy to ionize the gases of interest.
  • the largest group of compounds measured by a PID are the organics (compounds containing carbon), and they can typically be measured to parts per million (ppm) concentrations. PIDs do not measure any gases with an IP greater than 11.7 eV, such as nitrogen, oxygen, carbon dioxide and water vapor.
  • the CRC Press Handbook of Chemistry and Physics includes a table listing the [Ps for various gases.
  • PIDs are sensitive (low ppm), low cost, fast responding, portable detectors. They also consume little power.
  • SAW Surface Acoustic Wave Sensors
  • SAW sensors are constructed with interdigitated metal electrodes fabricated on piezoelectric substrates both to generate and to detect surface acoustic waves.
  • Surface acoustic waves are waves that have their maximum amplitude at the surface and whose energy is nearly all contained within 15 to 20 wavelengths of the surface. Because the amplitude is a maximum at the surface such devices are very surface sensitive.
  • SAW devices are used as electronic bandpass filters in cell phones. They are hermetically packaged to insure that their performance will not change due to a substance contacting the surface of the SAW.
  • SAW chemical sensors take advantage of this surface sensitivity to function as sensors.
  • SAW devices are frequently coated with a thin polymer film that will affect the frequency and insertion loss of the device in a predictable and reproducible manner.
  • Each sensor in a sensor array is coated with a different polymer and the number and type of polymer coating are selected based on the chemical to be detected. If the device with the polymer coating is then subjected to chemical vapors that absorb into the polymer material, then the frequency and insertion loss of the device will further change. It is this final change that allows the device to function as a chemical sensor.
  • SAW devices are each coated with a different polymer material, the response to a given chemical vapor will vary from device to device.
  • the polymer films are normally chosen so that each will have a different chemical affinity for a variety of organic chemical classes, that is, hydrocarbon, alcohol, ketone, oxygenated, chlorinated, and nitrogenated. If the polymer films are properly chosen, each chemical vapor of interest will have a unique overall effect on the set of devices.
  • SAW chemical sensors are useful in the range of organic compounds from hexane on the light, volatility extreme to semi-volatile compounds on the heavy, low volatility extreme.
  • the sensitivity of the system can be enhanced for low vapor concentrations by having the option of using a chemical preconcentrator before the array.
  • the preconcentrator absorbs the test vapors for a period of time and is then heated to release the vapors over a much shorter time span thereby increasing the effective concentration of the vapor at the array.
  • the system uses some type of drive and detection electronics for the array.
  • An on board microprocessor is used to control the sequences of the system and provide the computational power to interpret and analyze data from the array.
  • SAW sensors are reasonably priced (less than $ 200 ) and have good sensitivity (tens of ppm) with very good selectivity. They are portable, robust and consume nominal power. They warm up in less than two minutes and require less than one minute for most analysis. They are typically not used in high accuracy quantitative applications, and thus require no calibration. SAW sensors do not drift over time, have a long operating life (greater than five years) and have no known shelf life issues. They are sensitive to moisture, but this is addressed with the use of a thermally desorbed concentrator and processing algorithms.
  • Sensors can use fluorescent polymers that react with volatile chemicals as sensitive target marker detectors.
  • Conventional fluorescence detection normally measures an increase or decrease in fluorescence intensity or an emission wavelength shift that occurs when a single molecule of the target marker interacts with an isolated chromophore, where the chromophore that interacts with the target marker is quenched; the remaining chromophores continue to fluoresce.
  • Fiber optic microsphere technology is based upon an array of a plurality of microsphere sensors (beads), wherein each microsphere belongs to a discrete class that is associated with a target marker, that is placed on an optical substrate containing a plurality of micrometer-scale wells (see, for example, Michael et al., Anal Chem, 71:2192-2198 (1998); Dickinson et al., Anal Chem., 71:2192-2198 (1999); Albert and Walt, Anal Chem, 72:1947-1955 (2000); and Stitzel et al., Anal Chem, 73:5266-5271 (1001), all of which are incorporated herein by reference in their entirety).
  • Each type of bead is encoded with a unique signature to identify the bead as well as its location.
  • the beads Upon exposure to a target marker, the beads respond to the target marker and their intensity and wavelength shifts are used to generate fluorescence response patterns, which are, in turn, compared to known patterns to identify the target marker.
  • Interdigitated microelectrode arrays are based on the used of a transducer film that incorporates an ensemble of nanometer-sized metal particles, each coated by an organic monomolecular layer shell (see, for example, Wohltjen and Snow, Anal Chem, 70:2856-2859 (1998); and Jarvis et al., Proceedings of the 3 rd Intl Aviation Security Tech Symposium, Atlantic City, N.J., 639-647 (2001), both of which are incorporated herein by reference in their entirety).
  • Such sensor devices are also known as metal-insulator-metal ensembles (MIME) because of the combination of a large group of colloidal-sized, conducting metal cores separated by thin insulating layers.
  • MIME metal-insulator-metal ensembles
  • MEMS Microelectromechanical Systems
  • Sensor technology based on MEMS integrate mechanical elements, sensors, actuators, and electronics on a common silicon substrate for use in detecting target markers (see, for example, Pinnaduwage et al., Proceedings of 3 rd Intl Aviation Security Tech Symposium, Atlantic City, N.J., 602-615 (2001); and Lareau et al., Proceedings of 3 rd Intl Aviation Security Tech Symposium, Atlantic City, N.J., 332-339 (2001), both of which are incorporated herein by reference in their entirety).
  • microcantilever sensors are hairlike, silicon-based devices that are at least 1 , 000 times more sensitive and smaller than currently used sensors.
  • the working principle for most microcantilever sensors is based on a measurement of displacement.
  • the displacement of a cantilever-probe is related to the binding of molecules on the (activated) surface of the cantilever beam, and is used to compute the strength of these bonds, as well as the presence of specific reagents in the solution under consideration (Fritz, J. et al., “Translating biomolecular recognition into nanomechanics,” Science, 288:316-318 (2000); Raiteri, R.
  • microcantilever technology uses silicon cantilever beams (preferably a few hundred micrometers long and 1 ⁇ thick) that are coated with a different sensor/detector layer (such as antibodies or aptamers). When exposed to a target marker, the cantilever surface absorbs the target marker, which leads to interfacial stress between the sensor and the absorbing layer that bends the cantilever. Each cantilever bends in a characteristic way typical for each target marker. From the magnitude of the cantilever's bending response as a function of time, a fingerprint pattern for each target marker can be obtained.
  • Microcantilever sensors are highly advantageous in that they can detect and measure relative humidity, temperature, pressure, flow, viscosity, sound, ultraviolet and infrared radiation, chemicals, and biomolecules such as DNA, proteins, and enzymes. Microcantilever sensors are rugged, reusable, and extremely sensitive, yet they cost little and consume little power. Another advantage in using the sensors is that they work in air, vacuum, or under liquid environments.
  • Molecular imprinting is a process of template-induced formation of specific molecular recognition sites (binding or catalytic) in a polymeric material where the template directs the positioning and orientation of the polymeric material's structural components by a self-assembling mechanism (see, for example, Olivier et al., Anal Bioanal Chem, 382:947-956 (2005); and Ersoz et al., Biosensors & Bioelectronics, 20:2197-2202 (2005), both of which are incorporated herein by reference in their entirety).
  • the polymeric material can include organic polymers as well as inorganic silica gels.
  • MIPs Molecularly imprinted polymers
  • sensor platforms including, but not limited to, fluorescence spectroscopy; UV/Vis spectroscopy; infrared spectroscopy; surface plasmon resonance; chemiluminescent adsorbent assay; and reflectometric interference spectroscopy.
  • An elderly patient with a history of insulin dependent diabetes requires a serious operation in which significant blood loss is anticipated.
  • the anesthesiologist continuously monitors exhaled breath glucose and lactic acid.
  • Several recent medical research studies have shown that tight control of glucose in the normal range improves outcome, wound healing and rate of post-operative infection in persons with diabetes.
  • the anesthesiologist can only monitor blood glucose intermittently by drawing blood samples. These results guide the administration of insulin. Excessive doses can lead to hypoglycemia, with disastrous consequences and inadequate doses can lead to hyperglycemia, which can result in intra- and post-operative complications.
  • Exhaled breath affords the potential of continuous tight glucose control without the potential for either hyperglycemia or hypoglycemia.
  • a “closed loop” system is possible where the exhaled breath glucose concentration is used to control and insulin infusion, thus freeing the anesthesiologist of having to give boluses of insulin.
  • the anesthesiologist monitors exhaled breath lactic acid to determine whether there is excessive blood loss or other reasons for decrease perfusion of vital organs.
  • blood pressure, heart rate and on occasions, central venous pressure are used to monitor patients for blood loss with resulting hypovolemia and diminished perfusion. This in turn leads to lactic acidosis, an ominous complication, but presently lactic acid can only be measured intermittently from blood samples.
  • the anesthesiologist will have a much better means of determining if there is hypoperfusion of vital organs.
  • measurement of compounds continuously in exhaled breath in either the gaseous or condensed state can lead to marked improvement in monitoring, and therefore, treatment of patients in the operating room and the intensive care unit.
  • the marker detection method of the present invention is intended to cover detection not only through the exhalation by a patient with a device utilizing electronic nose technology, but also other suitable technologies, such as gas chromatography, transcutaneous/transdermal detection, semiconductive gas sensors, mass spectrometers, IR or UV or visible or fluorescence spectrophotometers.

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US11/301,911 US20070167853A1 (en) 2002-01-22 2005-12-13 System and method for monitoring health using exhaled breath
US11/512,856 US8211035B2 (en) 2002-01-22 2006-08-29 System and method for monitoring health using exhaled breath
EP06849923A EP1960775A4 (fr) 2005-12-13 2006-12-06 Système et procédé de suivi de santé utilisant l'air exhalé
CA002633826A CA2633826A1 (fr) 2005-12-13 2006-12-06 Systeme et procede de suivi de sante utilisant l'air exhale
JP2008545656A JP2009519467A (ja) 2005-12-13 2006-12-06 呼息を用いて健康をモニタリングするためのシステムおよび方法
PCT/US2006/046660 WO2007089328A2 (fr) 2005-12-13 2006-12-06 Système et procédé de suivi de santé utilisant l'air exhalé
US13/246,436 US20120016252A1 (en) 2002-01-22 2011-09-27 System and method for monitoring health using exhaled breath

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US10/054,619 US7104963B2 (en) 2002-01-22 2002-01-22 Method and apparatus for monitoring intravenous (IV) drug concentration using exhaled breath
US10/178,877 US6981947B2 (en) 2002-01-22 2002-06-24 Method and apparatus for monitoring respiratory gases during anesthesia
US10/788,501 US20050054942A1 (en) 2002-01-22 2004-02-26 System and method for therapeutic drug monitoring
PCT/US2005/006355 WO2005098429A2 (fr) 2000-11-08 2005-02-28 Systeme et procede de diagnostic, de traitement et de pharmacovigilance therapeutique en temps reel
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Cited By (117)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070287359A1 (en) * 2004-02-26 2007-12-13 Pixen Inc. Diagnostic Sensor
US20080028632A1 (en) * 2006-04-24 2008-02-07 Daniel Py Needle penetrable and laser resealable lyophilization device and related method
US20080045825A1 (en) * 2006-08-15 2008-02-21 Melker Richard J Condensate glucose analyzer
US20080091116A1 (en) * 2004-03-31 2008-04-17 Mats Cardell Arrangement for Analysing Respiratory Gases
US20090012216A1 (en) * 2006-03-15 2009-01-08 Toshiyuki Yamauchi Stabilized Polyolefin-Based Resin and Polyolefin-Based Resin Stabilization Process
US20090028800A1 (en) * 2007-07-27 2009-01-29 Peeples William H Method of Treating Postpartum Depression and Aggression
US20090032695A1 (en) * 2006-06-09 2009-02-05 Kaye William J Miniaturized Ion Mobility Spectrometer
US20090271375A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20090271122A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20090271009A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment modification methods and systems
US20090267758A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems and apparatus for measuring a bioactive agent effect
US20090271219A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The Stste Of Delaware Methods and systems for presenting a combination treatment
US20090271213A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20090269329A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination Therapeutic products and systems
US20090271217A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Side effect ameliorating combination therapeutic products and systems
US20090271008A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment modification methods and systems
US20090271215A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for detecting a bioactive agent effect
US20090270694A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20090270688A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting a combination treatment
US20090270693A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for modifying bioactive agent use
US20090271347A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US20090271011A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US20090292676A1 (en) * 2008-04-24 2009-11-26 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20090312595A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware System and method for memory modification
US20090312668A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20090319301A1 (en) * 2008-04-24 2009-12-24 Searete Llc, A Limited Liability Corporation Of The State Of Delawar Methods and systems for presenting a combination treatment
US20100004762A1 (en) * 2008-04-24 2010-01-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100017001A1 (en) * 2008-04-24 2010-01-21 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100022820A1 (en) * 2008-04-24 2010-01-28 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100042578A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100041964A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20100041958A1 (en) * 2008-04-24 2010-02-18 Searete Llc Computational system and method for memory modification
US20100050744A1 (en) * 2008-08-26 2010-03-04 Honeywell International Inc. Multi-sensor Gas Detectors
US20100063368A1 (en) * 2008-04-24 2010-03-11 Searete Llc, A Limited Liability Corporation Computational system and method for memory modification
US20100069724A1 (en) * 2008-04-24 2010-03-18 Searete Llc Computational system and method for memory modification
US20100076249A1 (en) * 2008-04-24 2010-03-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100081860A1 (en) * 2008-04-24 2010-04-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US20100100036A1 (en) * 2008-04-24 2010-04-22 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US20100101571A1 (en) * 2008-10-28 2010-04-29 General Electric Company Anesthesia system and method
US20100125561A1 (en) * 2008-04-24 2010-05-20 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100130811A1 (en) * 2008-04-24 2010-05-27 Searete Llc Computational system and method for memory modification
US20100154245A1 (en) * 2003-04-28 2010-06-24 Daniel Py Lyophilization method and device
US20100241019A1 (en) * 2009-03-18 2010-09-23 Cardinal Health 207, Inc. Exhaled breath condensate biometric marker measurement apparatus and method
WO2010121072A1 (fr) * 2009-04-15 2010-10-21 Nanomix, Inc. Détecteur et analyseur d'haleine et analyseur/détecteur d'haleine combiné
US20100280332A1 (en) * 2008-04-24 2010-11-04 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US20100297635A1 (en) * 2007-10-02 2010-11-25 Anna-Carin Olin Collection and measurement of exhaled particles
US20110098590A1 (en) * 2009-10-26 2011-04-28 Pulse Health Llc Methods and apparatuses for detecting analytes
US20110105856A1 (en) * 2009-10-29 2011-05-05 Robyn Aylor Haines Diagnostic testing
US20110224950A1 (en) * 2003-12-31 2011-09-15 Sieracki Jeffrey M Indirect Monitoring of Device Usage and Activities
US20110270053A1 (en) * 2004-05-28 2011-11-03 David Scott Utley Intra-Oral Detector and System for Modification of Undesired Behaviors and Methods Thereof
US20110313306A1 (en) * 2010-06-16 2011-12-22 Sociedad Europea de Analisis Diferencial de Movilidad Method and apparatus for monitoring stress levels or sudden changes of humor in humans or other individuals in real time by means of vapor analysis
US20120016252A1 (en) * 2002-01-22 2012-01-19 Melker Richard J System and method for monitoring health using exhaled breath
KR101119594B1 (ko) * 2010-08-13 2012-03-06 경북대학교 산학협력단 폐질환 환자의 호기측정 시스템 및 방법
US20120136269A1 (en) * 2010-11-26 2012-05-31 Kurt Peter Weckstrom Liquid separation apparatus for removing a liquid from a respiratory gas and respiratory gas analyzing system
US20120183949A1 (en) * 2011-01-19 2012-07-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method, device, or system using lung sensor for detecting a physiological condition in a vertebrate subject
US20120203126A1 (en) * 2009-10-22 2012-08-09 Koninklijke Philips Electronics N.V. Method and apparatus for measuring the concentration of a gas in exhaled air
US20120272713A1 (en) * 2011-04-29 2012-11-01 Theodosios Kountotsis Breath actuation of electronic and non-electronic devices for preventing unauthorized access
US8418523B2 (en) 2008-03-03 2013-04-16 Keith Lueck Calibration and accuracy check system for a breath tester
CN103097891A (zh) * 2010-05-31 2013-05-08 国立大学法人德岛大学 疾病重症度的检查方法
US20130168548A1 (en) * 2011-12-29 2013-07-04 General Electric Company Ion-based breath analysis system
US20130197384A1 (en) * 2012-02-01 2013-08-01 National Tsing Hua University Medical Ventilator Capable of Early Detecting and Recognizing Types of Pneumonia, Gas Recognition Chip, and Method for Recognizing Gas Thereof
US20150038940A1 (en) * 2012-03-13 2015-02-05 Universitaet Des Saarlandes Appliance for performing anaesthesia or analgosedation, and method for operating an appliance for performing anaesthesia or analgosedation
US9027552B2 (en) 2012-07-31 2015-05-12 Covidien Lp Ventilator-initiated prompt or setting regarding detection of asynchrony during ventilation
US9121844B1 (en) * 2008-09-09 2015-09-01 Sociedad Europea de Analisis Diferencial de Movilidad Method to analyze and classify persons and organisms based on odor patterns from released vapors
US20150265184A1 (en) * 2014-03-20 2015-09-24 Capnia, Inc. Selection, segmentation and analysis of exhaled breath for airway disorders assessment
WO2015191579A1 (fr) * 2014-06-11 2015-12-17 Integrated Monitoring Systems, Llc Système d'échantillonnage d'alcool respiratoire inviolable amovible
US20160151601A1 (en) * 2009-11-16 2016-06-02 Maquet Critical Care Ab Breathing apparatus with monitored delivery device
US20160158471A1 (en) * 2014-12-05 2016-06-09 Dance Biopharm, Inc. Integration of glucose data to adjust inhaled insulin dose
US20160287169A1 (en) * 2015-03-31 2016-10-06 Oulun Yliopisto Apparatus and method for electroencephalographic examination
US20170004958A1 (en) * 2011-11-17 2017-01-05 Ownstone Medical Limited Sensor apparatus and method for use with gas ionization systems
EP3207868A1 (fr) * 2016-02-19 2017-08-23 Patonomics AB Procédé et appareil permettant d'identifier un état émotionnel transitoire d'un mammifère vivant
US20170251952A1 (en) * 2016-03-04 2017-09-07 Government Of The United States As Represented By The Secretary Of The Air Force Exhaled breath hypoxia biomarkers
US9936897B2 (en) 2003-06-19 2018-04-10 Capnia, Inc. Breath end-tidal gas monitor
US9950129B2 (en) 2014-10-27 2018-04-24 Covidien Lp Ventilation triggering using change-point detection
KR20180060469A (ko) * 2016-11-29 2018-06-07 한국기계연구원 단일 호흡기체의 분석방법과 분석장치
US9993604B2 (en) 2012-04-27 2018-06-12 Covidien Lp Methods and systems for an optimized proportional assist ventilation
US10034621B2 (en) 2011-12-21 2018-07-31 Capnia, Inc. Collection and analysis of a volume of exhaled gas with compensation for the frequency of a breathing parameter
WO2018144373A1 (fr) * 2017-02-01 2018-08-09 Shire Human Genetic Therapies, Inc. Système et procédé de détection physiologique et d'administration d'un agent thérapeutique
CN108603871A (zh) * 2015-10-29 2018-09-28 英福康有限责任公司 使用气体调制的气体检测
CN109330598A (zh) * 2018-10-31 2019-02-15 上海健康医学院 一种基于符合探测原理的正电子核素实时计数检测仪
CN109813891A (zh) * 2017-11-18 2019-05-28 镇江亿特生物科技发展有限公司 一种检测氯丙嗪的时间分辨荧光免疫层析定量检测试纸条
US10362967B2 (en) 2012-07-09 2019-07-30 Covidien Lp Systems and methods for missed breath detection and indication
US10499819B2 (en) 2013-01-08 2019-12-10 Capnia, Inc. Breath selection for analysis
US10770182B2 (en) 2017-05-19 2020-09-08 Boston Scientific Scimed, Inc. Systems and methods for assessing the health status of a patient
US10852264B2 (en) 2017-07-18 2020-12-01 Boston Scientific Scimed, Inc. Systems and methods for analyte sensing in physiological gas samples
US10896749B2 (en) 2017-01-27 2021-01-19 Shire Human Genetic Therapies, Inc. Drug monitoring tool
US11081211B2 (en) 2013-06-20 2021-08-03 Baxalta Incorporated Method and apparatus for providing a pharmacokinetic drug dosing regimen
US11166636B2 (en) 2018-02-20 2021-11-09 Boston Scientific Scimed, Inc. Breath sampling mask and system
US11172846B2 (en) 2016-10-21 2021-11-16 Boston Scientific Scimed, Inc. Gas sampling device
US11191457B2 (en) 2016-06-15 2021-12-07 Boston Scientific Scimed, Inc. Gas sampling catheters, systems and methods
US11191449B2 (en) 2013-08-30 2021-12-07 Capnia, Inc. Neonatal carbon dioxide measurement system
US20220034764A1 (en) * 2018-12-03 2022-02-03 Mallinckrodt Hospital Products IP Unlimited Company Gas sensor module
US11262354B2 (en) 2014-10-20 2022-03-01 Boston Scientific Scimed, Inc. Disposable sensor elements, systems, and related methods
US11273283B2 (en) 2017-12-31 2022-03-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11324954B2 (en) 2019-06-28 2022-05-10 Covidien Lp Achieving smooth breathing by modified bilateral phrenic nerve pacing
US11331004B2 (en) 2013-02-12 2022-05-17 Capnia, Inc. Sampling and storage registry device for breath gas analysis
US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
US11442056B2 (en) 2018-10-19 2022-09-13 Regents Of The University Of Minnesota Systems and methods for detecting a brain condition
US11452839B2 (en) 2018-09-14 2022-09-27 Neuroenhancement Lab, LLC System and method of improving sleep
US11585750B2 (en) * 2017-11-06 2023-02-21 Henkel Ag & Co. Kgaa Arrangement for determining body surface properties by means of Multiple Spatially Resolved Reflection Spectroscopy (MSRRS)
US11636870B2 (en) 2020-08-20 2023-04-25 Denso International America, Inc. Smoking cessation systems and methods
US11662325B2 (en) 2018-12-18 2023-05-30 Regents Of The University Of Minnesota Systems and methods for measuring kinetic response of chemical sensor elements
US11691165B2 (en) 2011-10-27 2023-07-04 Copilot Ventures Fund Iii Llc Methods of delivery of encapsulated perfluorocarbon taggants
US11717686B2 (en) 2017-12-04 2023-08-08 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to facilitate learning and performance
US11723579B2 (en) 2017-09-19 2023-08-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement
US11760170B2 (en) 2020-08-20 2023-09-19 Denso International America, Inc. Olfaction sensor preservation systems and methods
US11760169B2 (en) 2020-08-20 2023-09-19 Denso International America, Inc. Particulate control systems and methods for olfaction sensors
US11786694B2 (en) 2019-05-24 2023-10-17 NeuroLight, Inc. Device, method, and app for facilitating sleep
US11813926B2 (en) 2020-08-20 2023-11-14 Denso International America, Inc. Binding agent and olfaction sensor
US11828210B2 (en) 2020-08-20 2023-11-28 Denso International America, Inc. Diagnostic systems and methods of vehicles using olfaction
US11835435B2 (en) 2018-11-27 2023-12-05 Regents Of The University Of Minnesota Systems and methods for detecting a health condition
WO2023240832A1 (fr) * 2022-06-14 2023-12-21 惠雨恩科技(深圳)有限公司 Dispositif d'acquisition d'expiration finale
US11881093B2 (en) 2020-08-20 2024-01-23 Denso International America, Inc. Systems and methods for identifying smoking in vehicles
US11921096B2 (en) 2019-09-10 2024-03-05 Regents Of The University Of Minnesota Fluid analysis system
US11918344B2 (en) * 2019-03-31 2024-03-05 Resmed Inc. Methods and apparatuses for analyzing one or more analytes from a user
US11932080B2 (en) 2020-08-20 2024-03-19 Denso International America, Inc. Diagnostic and recirculation control systems and methods
US12017506B2 (en) 2021-03-31 2024-06-25 Denso International America, Inc. Passenger cabin air control systems and methods

Families Citing this family (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2205298B1 (fr) * 2007-10-15 2020-07-15 The Secretary, Department Of Information Technology Système amélioré de délivrance automatique d'une anesthésie
EP2085107A1 (fr) * 2008-01-31 2009-08-05 General Electric Company Procédé et système pour l'administration d'anesthésie
WO2009086033A1 (fr) * 2007-12-20 2009-07-09 Dean Enterprises, Llc Détection d'états à partir du son
WO2010087874A1 (fr) * 2009-01-28 2010-08-05 Anazyme, Llc Compositions et méthodes pour le diagnostic des chocs
US8338127B2 (en) * 2008-01-31 2012-12-25 Anazyme Testing a mammal for presence, progression or stage of a shock condition
US9959471B2 (en) * 2008-05-06 2018-05-01 Careview Communications, Inc. Patient video monitoring systems and methods for thermal detection of liquids
US8172836B2 (en) * 2008-08-11 2012-05-08 Tyco Healthcare Group Lp Electrosurgical system having a sensor for monitoring smoke or aerosols
WO2010033724A2 (fr) 2008-09-19 2010-03-25 Dexcom, Inc. Membrane contenant des particules et électrode particulaire pour capteurs d’analytes
WO2010045465A1 (fr) * 2008-10-15 2010-04-22 The University Of Tennessee Research Foundation Procédé et dispositif de détection de la concentration d’un médicament biodisponible dans un fluide
US11375929B2 (en) 2008-10-15 2022-07-05 The University Of Tennessee Research Foundation Method and device for detection of bioavailable drug concentration in a fluid sample
US8256286B2 (en) * 2009-04-24 2012-09-04 Sober Steering Sensors, Llc System and method for detecting and measuring ethyl alcohol in the blood of a motorized vehicle driver transdermally and non-invasively in the presence of interferents
CA2760506A1 (fr) * 2009-04-29 2010-11-04 Pharmacophotonics, Inc. Capteur optique percutane auto-perforant utilise pour la detection optique de liquide intravasculaire
US20100324439A1 (en) * 2009-06-19 2010-12-23 Paul Wesley Davenport High frequency airway oscillation for exhaled air diagnostics
US20120196935A1 (en) * 2009-09-18 2012-08-02 The Regents Of The University Of California Methods for detecting autodigestion
US9420971B2 (en) 2009-10-24 2016-08-23 Carrot Sense, Inc. Extracorporeal devices and methods for facilitating cessation of undesired behaviors
AT509964B1 (de) * 2010-05-25 2014-07-15 Carbomed Medical Solutions Gmbh & Co Kg Vorrichtung und verfahren zur bestimmung einer fertilen phase einer frau durch ermittlung eines co2-partialdruckes in einem atemgas der frau
TW201239337A (en) * 2010-11-26 2012-10-01 Global Fiberoptics Ltd Optical rotation measurement device, optical rotation measurement method that can be used in optical rotation measurement system, optical rotation measurement optical system, and sample cell for optical rotation measurement
US20120277612A1 (en) * 2011-04-27 2012-11-01 General Electric Company Systems for intravenous drug monitoring
US9750430B2 (en) * 2011-04-27 2017-09-05 General Electric Company Methods of intravenous drug monitoring
US20140330152A1 (en) * 2011-05-09 2014-11-06 Ilan Keidan Providing evidence whether an intravascular conduit is correctly positioned
US20130066349A1 (en) * 2011-09-13 2013-03-14 Applied Nanotech Holdings, Inc. Stimulated voc characterization
WO2013056154A1 (fr) * 2011-10-13 2013-04-18 University Of Houston System Appareil et procédé d'amélioration de seuil d'entraînement
EP2856133B1 (fr) 2012-06-01 2018-05-09 The University of Tennessee Research Foundation Procédé et dispositif améliorés pour la détection de la concentration d'un médicament bio-disponible
US9733644B2 (en) 2012-07-17 2017-08-15 Elwha Llc Unmanned device interaction methods and systems
US10019000B2 (en) 2012-07-17 2018-07-10 Elwha Llc Unmanned device utilization methods and systems
CN103048382B (zh) * 2012-12-21 2015-02-11 浙江大学 在线监测异丙酚麻醉药的系统和方法
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US20140288454A1 (en) * 2013-03-14 2014-09-25 Pulmonary Analytics Method For Using Exhaled Breath to Determine the Presence of Drug
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
WO2014173558A1 (fr) 2013-04-24 2014-10-30 Fresenius Kabi Deutschland Gmbh Méthode de fonctionnement d'un dispositif de commande pour le contrôle d'un dispositif de perfusion
CA2919892C (fr) 2013-08-12 2019-06-18 Pharmaceutical Manufacturing Research Services, Inc. Comprime extrude anti-abus a liberation immediate
GB2517702A (en) 2013-08-28 2015-03-04 Ibm Collaborative electronic nose management in personal devices
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
EP2905618A1 (fr) * 2014-02-05 2015-08-12 Roche Diagnostics GmbH Utilisation de métaux rares comme composants clés
JP2015232654A (ja) * 2014-06-10 2015-12-24 セイコーエプソン株式会社 呼気検出装置、携帯端末および時刻表示装置
AU2015290098B2 (en) 2014-07-17 2018-11-01 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CA2964628A1 (fr) 2014-10-20 2016-04-28 Pharmaceutical Manufacturing Research Services, Inc. Forme galenique anti-abus de remplissage de liquide a liberation prolongee
DE102014015897A1 (de) * 2014-10-28 2016-04-28 Drägerwerk AG & Co. KGaA Verfahren und System zum Kontrollieren einer Medikamentendosiereinrichtung
US10206572B1 (en) 2017-10-10 2019-02-19 Carrot, Inc. Systems and methods for quantification of, and prediction of smoking behavior
EP3280329B1 (fr) 2015-04-07 2023-11-15 McNeil AB Systèmes et procédés de quantification et de prédiction d'un comportement tabagique
US10537285B2 (en) 2016-03-04 2020-01-21 Masimo Corporation Nose sensor
US10993662B2 (en) 2016-03-04 2021-05-04 Masimo Corporation Nose sensor
RU2608239C1 (ru) * 2016-04-12 2017-01-17 Общество с ограниченной ответственностью "Аби Девелопмент" Способ и система определения пригодности изображения документа для оптического распознавания символов и других операций по обработке изображений
US10132752B2 (en) 2017-01-27 2018-11-20 The United States Of America, As Represented By The Secretary Of The Navy Hand-held laser biosensor
CN107137085B (zh) * 2017-04-01 2019-08-27 浙江大学 一种呼吸状态检测方法及无线无源的柔性声表面波传感器
CN107041751A (zh) * 2017-04-01 2017-08-15 浙江大学 一种呼吸状态检测系统及无线无源的声表面波传感器
WO2018194992A1 (fr) 2017-04-18 2018-10-25 Masimo Corporation Capteur de nez
CN109813793A (zh) * 2017-11-21 2019-05-28 中国科学院大连化学物理研究所 一种七氟烷的离子迁移谱检测方法
WO2019173561A1 (fr) * 2018-03-08 2019-09-12 Graham Nichol Dispositifs, systèmes et procédés pour l'administration d'un médicament de modification de lésion de reperfusion à un patient
US11315686B2 (en) * 2018-08-07 2022-04-26 Vivante Health, Inc. Individualized care management system based on digestive activity
EP3846691A4 (fr) * 2018-09-03 2022-06-15 Kozhnosys Private Limited Système de détection de composés organiques volatils (voc) dans l'haleine exhalée pour la surveillance de la santé
RU2688724C1 (ru) * 2018-12-05 2019-05-22 Федеральное государственное бюджетное военное образовательное учреждение высшего образования "Военно-медицинская академия имени С.М. Кирова" Министерства обороны Российской Федерации (ВМедА) Система измерения энергетических затрат организма в экстремальных условиях
WO2020131355A2 (fr) * 2018-12-18 2020-06-25 Analog Devices, Inc. Système portable basé sur le nuage pour la mesure non invasive de la glycémie en temps réel
CA3166398A1 (fr) 2019-12-30 2021-07-08 Cilag Gmbh International Systemes et procedes d'aide a des individus dans un programme de changement comportemental
JP6846584B1 (ja) * 2020-01-22 2021-03-24 株式会社汀線科学研究所 呼気終末濃度測定装置
US20210386142A1 (en) * 2020-06-12 2021-12-16 Utah Valley University System for molecular imprinted protective face mask
US20210386133A1 (en) * 2020-06-12 2021-12-16 Utah Valley University Apparatus for a molecular imprinted protective face mask
EP4181781A1 (fr) * 2020-07-16 2023-05-24 Universitäts-Kinderspital beider Basel Procédé de suivi thérapeutique des médicaments basé sur haleine
CN113092544B (zh) * 2021-04-08 2024-02-20 青岛大学 级次结构氧化铋材料在气体检测中的应用
USD997365S1 (en) 2021-06-24 2023-08-29 Masimo Corporation Physiological nose sensor
DE102021213970A1 (de) 2021-12-08 2023-06-15 Zf Friedrichshafen Ag Computer-implementiertes Verfahren und Vorrichtung zum Zuordnen einer Geruchssubtanz eines zu untersuchenden Gases zu einem elektrischen Geruchssignal
US11977025B2 (en) 2022-07-07 2024-05-07 Ge Infrastructure Technology Llc System and method for on-board data analysis for multi-gas sensing

Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3567029A (en) * 1969-08-26 1971-03-02 Babington A Quame Column for testing biological fluids
US3649199A (en) * 1970-03-26 1972-03-14 Varian Associates Method for detecting trace quantities of an organic drug material in a living animal
US3792272A (en) * 1973-01-12 1974-02-12 Omicron Syst Corp Breath test device for organic components, including alcohol
US3877291A (en) * 1972-08-15 1975-04-15 Borg Warner Portable breath tester
US3951607A (en) * 1974-11-29 1976-04-20 Searle Cardio-Pulmonary Systems Inc. Gas analyzer
US3955926A (en) * 1972-02-12 1976-05-11 Merck Patent Gesellschaft Mit Beschrankter Haftung Process and quick-action reagent for the detection of narcotics
US4150670A (en) * 1977-11-14 1979-04-24 University Patents, Inc. Anesthesia detector and display apparatus
US4202352A (en) * 1978-04-06 1980-05-13 Research Development Corporation Apparatus for measurement of expired gas concentration in infants
US4215409A (en) * 1978-03-13 1980-07-29 Mckesson Company Flow control system for anesthesia apparatus
US4312228A (en) * 1979-07-30 1982-01-26 Henry Wohltjen Methods of detection with surface acoustic wave and apparati therefor
US4314564A (en) * 1979-02-22 1982-02-09 Dragerwerk Aktiengesellschaft Method and apparatus for determining alcohol concentration in the blood
US4334540A (en) * 1979-05-01 1982-06-15 Monell Chemical Senses Center Method of diagnosing periodontal disease through the detection of pyridine compounds
US4432226A (en) * 1982-02-05 1984-02-21 Dempster Philip T Method and apparatus for measuring gaseous oxygen
US4456014A (en) * 1983-01-03 1984-06-26 Thoratec Laboratories Corporation Flow restrictor
US4734777A (en) * 1982-12-07 1988-03-29 Canon Kabushiki Kaisha Image pick-up apparatus having an exposure control device
US4735777A (en) * 1985-03-11 1988-04-05 Hitachi, Ltd. Instrument for parallel analysis of metabolites in human urine and expired air
US4796639A (en) * 1987-11-05 1989-01-10 Medical Graphics Corporation Pulmonary diagnostic system
US4895017A (en) * 1989-01-23 1990-01-23 The Boeing Company Apparatus and method for early detection and identification of dilute chemical vapors
US4938928A (en) * 1986-10-28 1990-07-03 Figaro Engineering Inc. Gas sensor
US4992244A (en) * 1988-09-27 1991-02-12 The United States Of America As Represented By The Secretary Of The Navy Films of dithiolene complexes in gas-detecting microsensors
US5003985A (en) * 1987-12-18 1991-04-02 Nippon Colin Co., Ltd. End tidal respiratory monitor
US5034192A (en) * 1984-11-23 1991-07-23 Massachusetts Institute Of Technology Molecule-based microelectronic devices
US5082630A (en) * 1990-04-30 1992-01-21 The United States Of America As Represented By The United States Department Of Energy Fiber optic detector for immuno-testing
US5081871A (en) * 1989-02-02 1992-01-21 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Breath sampler
US5094235A (en) * 1989-05-10 1992-03-10 Dragerwerk Aktiengesellschaft Anesthesia ventilating apparatus having a breathing circuit and control loops for anesthetic gas components
US5111827A (en) * 1988-02-11 1992-05-12 Instrumentarium Corp. Respiratory sampling device
US5179027A (en) * 1991-01-10 1993-01-12 Fisher Murray M Method employing chemical markers and kit for verifying the source and completeness of urine samples for testing for the presence of drugs of abuse
US5231591A (en) * 1989-09-11 1993-07-27 Nellcor Incorporated Agent gas analyzer and method of use
US5296706A (en) * 1992-12-02 1994-03-22 Critikon, Inc. Shutterless mainstream discriminating anesthetic agent analyzer
US5303575A (en) * 1993-06-01 1994-04-19 Alcotech Research Inc. Apparatus and method for conducting an unsupervised blood alcohol content level test
US5317506A (en) * 1989-01-30 1994-05-31 Abbott Laboratories Infusion fluid management system
US5317156A (en) * 1992-01-29 1994-05-31 Sri International Diagnostic tests using near-infrared laser absorption spectroscopy
US5409839A (en) * 1993-11-01 1995-04-25 International Electronic Technology Corp. Method of tagging and detecting drugs, crops, chemical compounds and currency with perfluorocarbon tracers (PFT'S)
US5425374A (en) * 1992-06-03 1995-06-20 Hideo Ueda Device and method for expiratory air examination
US5482601A (en) * 1994-01-28 1996-01-09 Director-General Of Agency Of Industrial Science And Technology Method and device for the production of carbon nanotubes
US5495744A (en) * 1993-10-25 1996-03-05 Kyoto Dai-Ichi Kagaku Co., Ltd. Method of correcting componential concentration in expiration and expiration analyzer
US5501212A (en) * 1991-09-25 1996-03-26 Siemens Aktiengesellschaft In-line dehumidifying device exposed to the ambient environment
US5528924A (en) * 1993-11-29 1996-06-25 Leybold Inficon Inc. Acoustic tool for analysis of a gaseous substance
US5605612A (en) * 1993-11-11 1997-02-25 Goldstar Electron Co., Ltd. Gas sensor and manufacturing method of the same
US5634517A (en) * 1994-01-27 1997-06-03 Siemens-Elema Ab Device for reducing the relative humidity of a flowing gas
US5716852A (en) * 1996-03-29 1998-02-10 University Of Washington Microfabricated diffusion-based chemical sensor
US5756879A (en) * 1996-07-25 1998-05-26 Hughes Electronics Volatile organic compound sensors
US5771890A (en) * 1994-06-24 1998-06-30 Cygnus, Inc. Device and method for sampling of substances using alternating polarity
US5861254A (en) * 1997-01-31 1999-01-19 Nexstar Pharmaceuticals, Inc. Flow cell SELEX
US5866434A (en) * 1994-12-08 1999-02-02 Meso Scale Technology Graphitic nanotubes in luminescence assays
US5891398A (en) * 1995-03-27 1999-04-06 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US5900552A (en) * 1997-03-28 1999-05-04 Ohmeda Inc. Inwardly directed wave mode ultrasonic transducer, gas analyzer, and method of use and manufacture
US5918257A (en) * 1993-09-17 1999-06-29 Alpha M.O.S. Methods and devices for the detection of odorous substances and applications
US6010459A (en) * 1996-04-09 2000-01-04 Silkoff; Philip E. Method and apparatus for the measurement of components of exhaled breath in humans
US6025200A (en) * 1996-12-21 2000-02-15 Tracer Detection Technology Corp. Method for remote detection of volatile taggant
US6057162A (en) * 1997-03-07 2000-05-02 Thermedics Detection, Inc. Disease diagnosis by vapor sample analysis
US6063243A (en) * 1995-02-14 2000-05-16 The Regents Of The Univeristy Of California Method for making nanotubes and nanoparticles
US6067167A (en) * 1998-08-10 2000-05-23 Innovative Lasers Corp. ILS sensors for drug detection within vehicles
US6074345A (en) * 1998-10-27 2000-06-13 University Of Florida Patient data acquisition and control system
US6180414B1 (en) * 1997-01-03 2001-01-30 Oridion Medical Ltd. Breath test for detection of drug metabolism
US6186977B1 (en) * 1997-04-24 2001-02-13 Joseph L. Riley Anesthesia Associates Apparatus and method for total intravenous anesthesia delivery and associated patient monitoring
US6190858B1 (en) * 1997-01-02 2001-02-20 Osmetech Plc Detection of conditions by analysis of gases or vapors
US6203814B1 (en) * 1994-12-08 2001-03-20 Hyperion Catalysis International, Inc. Method of making functionalized nanotubes
US6216690B1 (en) * 1997-10-15 2001-04-17 Datex-Ohmeda, Inc. Method and apparatus for rapid control of set inspired gas concentration in anesthesia delivery systems
US6221026B1 (en) * 1999-01-12 2001-04-24 Michael Phillips Breath test for the detection of various diseases
US6234006B1 (en) * 1998-03-20 2001-05-22 Cyrano Sciences Inc. Handheld sensing apparatus
US6237397B1 (en) * 1999-10-06 2001-05-29 Iowa State University Research Foundation, Inc. Chemical sensor and coating for same
US6244096B1 (en) * 1998-06-19 2001-06-12 California Institute Of Technology Trace level detection of analytes using artificial olfactometry
US6248078B1 (en) * 1998-08-31 2001-06-19 Johns Hopkins University Volatile biomarkers for analysis of hepatic disorders
US6251082B1 (en) * 1995-02-06 2001-06-26 Ntc Technology, Inc. Non-invasive estimation of arterial blood gases
US20020007249A1 (en) * 2000-02-22 2002-01-17 Cranley Paul E. Personal computer breath analyzer for health-related behavior modification and method
US20020007687A1 (en) * 1999-03-24 2002-01-24 Ralf Zimmermann Method for detecting trace substances and/or environmental properties
US6341520B1 (en) * 1996-08-13 2002-01-29 Suzuki Motor Corporation Method and apparatus for analyzing breath sample
US20020014236A1 (en) * 2000-03-25 2002-02-07 Ralf Dittmann Arrangement and process for controlling a numerical value for patient respiration
US20020017300A1 (en) * 2000-06-13 2002-02-14 Hickle Randall S. Apparatus and method for mask free delivery of an inspired gas mixture and gas sampling
US20020026937A1 (en) * 2000-08-28 2002-03-07 Mault James R. Respiratory gas sensors in folw path
US20020034757A1 (en) * 1998-05-20 2002-03-21 Cubicciotti Roger S. Single-molecule selection methods and compositions therefrom
US6363772B1 (en) * 1999-12-10 2002-04-02 Quadrivium, L.L.C. System and method for detection of a biological condition
US6371114B1 (en) * 1998-07-24 2002-04-16 Minnesota Innovative Technologies & Instruments Corporation Control device for supplying supplemental respiratory oxygen
US6387329B1 (en) * 1998-11-16 2002-05-14 California Institute Of Technology Use of an array of polymeric sensors of varying thickness for detecting analytes in fluids
US6399302B1 (en) * 1998-08-21 2002-06-04 University Of Virginia Patent Foundation Signal generating oligonucleotide-based biosensor
US20020068295A1 (en) * 2000-07-13 2002-06-06 Marc Madou Multimeric biopolymers as structural elements and sensors and actuators in microsystems
US20030004426A1 (en) * 2001-05-24 2003-01-02 Melker Richard J. Method and apparatus for detecting environmental smoke exposure
US20030008407A1 (en) * 2001-03-03 2003-01-09 Fu Chi Yung Non-invasive diagnostic and monitoring system based on odor detection
US6511453B2 (en) * 1997-03-10 2003-01-28 Michael Georgieff Device for controlled anaesthesia, analgesia and/or sedation
US20030023180A1 (en) * 2001-07-26 2003-01-30 Mault James R. Respiratory analyzer and method for measuring changes in concentration of a gas component of a breathing gas mixture
US20030059820A1 (en) * 1997-11-26 2003-03-27 Tuan Vo-Dinh SERS diagnostic platforms, methods and systems microarrays, biosensors and biochips
US6558626B1 (en) * 2000-10-17 2003-05-06 Nomadics, Inc. Vapor sensing instrument for ultra trace chemical detection
US20030087239A1 (en) * 2000-09-13 2003-05-08 Marty Stanton Target activated nucleic acid biosensor and methods of using same
US20030119065A1 (en) * 2001-12-21 2003-06-26 Industrial Technology Research Institute Peptide and amine examination method using the same
US6680377B1 (en) * 1999-05-14 2004-01-20 Brandeis University Nucleic acid-based detection
US20040027246A1 (en) * 2002-08-09 2004-02-12 S.I.E.M. S.R.L. Portable device with sensors for signalling physiological data
US20040038386A1 (en) * 2000-09-04 2004-02-26 Wolfgang Zesch Multianalyte determination system and methods
US6727075B2 (en) * 1998-12-02 2004-04-27 The Trustees Of The University Of Pennsylvania Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases
US20040101477A1 (en) * 2002-11-27 2004-05-27 Xanthus Life Sciences, Inc. Individualization of therapy with anesthetics
US6755783B2 (en) * 1999-04-16 2004-06-29 Cardiocom Apparatus and method for two-way communication in a device for monitoring and communicating wellness parameters of ambulatory patients
US6807965B1 (en) * 1998-06-03 2004-10-26 Scott Laboratories, Inc. Apparatus and method for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures
US20050037374A1 (en) * 1999-11-08 2005-02-17 Melker Richard J. Combined nanotechnology and sensor technologies for simultaneous diagnosis and treatment
US20050054942A1 (en) * 2002-01-22 2005-03-10 Melker Richard J. System and method for therapeutic drug monitoring
US20050065446A1 (en) * 2002-01-29 2005-03-24 Talton James D Methods of collecting and analyzing human breath
USRE38728E1 (en) * 1997-09-11 2005-04-19 Oridion Medical, LTD Breath test analyzer
US20050083527A1 (en) * 2002-07-23 2005-04-21 Bryan Flaherty Disposable sensor for use in measuring an analyte in a gaseous sample
US6981947B2 (en) * 2002-01-22 2006-01-03 University Of Florida Research Foundation, Inc. Method and apparatus for monitoring respiratory gases during anesthesia
US7335164B2 (en) * 1996-07-15 2008-02-26 Ntc Technology, Inc. Multiple function airway adapter

Family Cites Families (103)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB829409A (en) 1956-04-30 1960-03-02 Governors Of The United Birmin Apparatus for sampling gas expired by a patient
US3608546A (en) 1970-01-21 1971-09-28 Gen Electric Fluidic spirometer
SE434438B (sv) 1980-02-21 1984-07-23 Gambro Engstrom Ab Anordning for detektering av forekomsten av en given gaskomponent i en gasblandning
US4361026A (en) 1980-06-24 1982-11-30 Muller Richard S Method and apparatus for sensing fluids using surface acoustic waves
US4346584A (en) 1980-10-20 1982-08-31 Boehringer John R Gas analyzer
US4349626A (en) 1980-10-28 1982-09-14 The Monell Chemical Senses Center Method of detecting Pseudomonas aeruginosa infections utilizing selected ketone and/or sulfur metabolites
US4534360A (en) 1983-05-27 1985-08-13 Williams Martin D Detection of lung cancer using breath luminescence
US4772559A (en) 1985-10-10 1988-09-20 Monell Chemical Senses Center Method of detecting the presence of bronchogenic carcinoma by analysis of expired lung air
EP0243470A1 (fr) 1985-10-25 1987-11-04 Corporation Autosense Systeme de caracterisation de la signature du souffle
GB8614515D0 (en) 1986-06-14 1986-07-23 Lion Lab Ltd Alcohol detecting devices
US5453359A (en) 1988-06-13 1995-09-26 American Biogenetic Sciences, Inc. Immunoassay and kit for in vitro detection of soluble DesAABB fibrin polymers
EP0370151A1 (fr) 1988-11-21 1990-05-30 L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude Procédé pour préparer des mélanges de gaz ayant une faible concentration et appareil pour leur production
EP0398286A3 (fr) 1989-05-18 1991-09-25 Nisshinbo Industries, Inc. Capteur d'ammoniac
US5071770A (en) 1989-09-05 1991-12-10 The United States Of America As Represented By The Secretary Of The Air Force Method for gaseous component indentification with #3 polymeric film
US5046018A (en) * 1989-09-11 1991-09-03 Nellcor, Inc. Agent gas analyzer and method of use
US5060506A (en) 1989-10-23 1991-10-29 Douglas David W Method and apparatus for monitoring the content of binary gas mixtures
US5254087A (en) * 1990-01-29 1993-10-19 Ivra Systems, Inc. Tourniquet apparatus for intravenous regional anesthesia
US5042501A (en) 1990-05-01 1991-08-27 Battelle Memorial Institute Apparatus and method for analysis of expired breath
US5145645A (en) 1990-06-15 1992-09-08 Spectral Sciences, Inc. Conductive polymer selective species sensor
US5167972A (en) 1990-09-04 1992-12-01 Wm. Wrigley Jr. Company Method of stabilizing peptide sweeteners in cinnamon-flavored chewing gums and confections
US5137692A (en) 1990-12-11 1992-08-11 Robert Fritz Nitrogen test kit for physical training
SE468416B (sv) 1991-09-27 1993-01-18 Lars Erik Gustafsson Saett att faststaella aktuell lungfunktion samt anordning foer att indikera naemnda lungfunktion
US5925014A (en) 1992-12-07 1999-07-20 Teeple Jr.; Edward Method and apparatus for preparing and administering intravenous anesthesia infusions
US5361771A (en) 1993-03-05 1994-11-08 Western Research Company, Inc. Portable pulmonary function testing device and method
US5465608A (en) 1993-06-30 1995-11-14 Orbital Sciences Corporation Saw vapor sensor apparatus and multicomponent signal processing
US5466700A (en) 1993-08-30 1995-11-14 Glaxo Wellcome Inc. Anesthetic use of N-phenyl-N-(4-piperidinyl)amides
DE69428173T2 (de) 1993-09-30 2002-03-28 Nittan Co Ltd Sensorvorrichtung und elektronische Anlage mit eingebauter Sensorvorrichtung
JP3838671B2 (ja) 1993-10-25 2006-10-25 アークレイ株式会社 呼気採取装置
US5547878A (en) 1993-11-02 1996-08-20 Kell; Michael Method of monitoring patient compliance with medications prescriptions
US5351522A (en) 1993-11-02 1994-10-04 Aequitron Medical, Inc. Gas sensor
US5776783A (en) 1993-11-02 1998-07-07 Private Clinic Laboratories, Inc. Method of monitoring therapeutic agent consumption
DE4339154C2 (de) 1993-11-16 1995-09-28 Hewlett Packard Gmbh Anästhesie-Protokolldatenverarbeitungssystem und Verfahren zum Steuern desselben
US5558083A (en) 1993-11-22 1996-09-24 Ohmeda Inc. Nitric oxide delivery system
US5325704A (en) * 1993-11-22 1994-07-05 The United States Of America As Represented By The Secretary Of The Army Surface acoustic wave (SAW) chemical multi-sensor array
DE4423289C1 (de) 1994-07-02 1995-11-02 Karlsruhe Forschzent Gassensor für reduzierende oder oxidierende Gase
US5571401A (en) 1995-03-27 1996-11-05 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US5573955A (en) 1995-06-05 1996-11-12 Microgenics Corp. Reducing tyramine interference in immunoassays for amphetamine and methamphetamine
FI102511B (fi) 1995-06-26 1998-12-31 Instrumentarium Oy Pitoisuusmittaus hengitysilmasta
US5645072A (en) 1995-09-28 1997-07-08 Thrall; Karla D. Real time chemical exposure and risk monitor
RU2104535C1 (ru) 1996-01-17 1998-02-10 Коган Алтар Хунович Способ определения просупероксидной активности выдыхаемого воздуха у больных и здоровых людей
GB9601186D0 (en) 1996-01-20 1996-03-20 Cleansharp Ltd Administration of Drugs
US5826577A (en) 1996-01-30 1998-10-27 Bacharach, Inc. Breath gas analysis module
DE19607646A1 (de) 1996-02-29 1997-09-11 Joerg Volkmann Cancolor - Schnelltest zur Erkennung von Cannabinoiden im Straßenverkehr
US5945069A (en) 1996-03-21 1999-08-31 California Institute Of Technology Gas sensor test chip
US5795787A (en) 1996-04-09 1998-08-18 Silkoff; Philip Method and apparatus for the measurement of exhaled nitric oxide in humans
FR2747027B1 (fr) 1996-04-09 1998-05-29 Cohen Laroque Emmanuel S Procede de determination de la profondeur d'anesthesie et dispositif pour la mise en oeuvre de ce procede
US5954685A (en) 1996-05-24 1999-09-21 Cygnus, Inc. Electrochemical sensor with dual purpose electrode
GB9618998D0 (en) * 1996-09-11 1996-10-23 Univ Glasgow Anaesthesia control
US6123072A (en) * 1996-09-11 2000-09-26 Downs; John B. Method and apparatus for breathing during anesthesia
US5783449A (en) 1996-10-25 1998-07-21 Kuznetsov; Oleg Method for quantifying alcohol catabolism
US5950630A (en) 1996-12-12 1999-09-14 Portwood; Michael T. System and method for improving compliance of a medical regimen
US6186958B1 (en) 1997-02-26 2001-02-13 Oridion Medical Breath test analyzer
US5996586A (en) 1997-03-26 1999-12-07 Phillips; Michael Breath test for detection of lung cancer
US5932877A (en) 1997-04-17 1999-08-03 Square One Technology, Inc. High performance side stream infrared gas analyzer
US6131571A (en) 1997-04-30 2000-10-17 University Of Florida Ventilation apparatus and anesthesia delivery system
WO1998057145A1 (fr) 1997-06-10 1998-12-17 Quadrivium, L.L.C. Systeme et methode de detection d'un etat biologique
US5958896A (en) 1997-08-08 1999-09-28 The Mclean Hospital Cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure
US6076392A (en) 1997-08-18 2000-06-20 Metasensors, Inc. Method and apparatus for real time gas analysis
GB2329245A (en) 1997-09-16 1999-03-17 Cavkit Ltd Generating a calibrating gas
US6007775A (en) 1997-09-26 1999-12-28 University Of Washington Multiple analyte diffusion based chemical sensor
US5928167A (en) 1997-10-20 1999-07-27 Metabolic Solutions, Inc. Blood test for assessing hepatic function
AU3909199A (en) 1997-12-15 1999-07-05 Nexstar Pharmaceuticals, Inc. Homogeneous detection of a target through nucleic acid ligand-ligand beacon interaction
CA2316887C (fr) 1997-12-31 2008-04-08 Alza Corporation Methode et systeme de controle osmotique de l'administration de medicament
US6598459B1 (en) 1998-01-09 2003-07-29 Chi Yung Fu Artificial olfactory system
US6094681A (en) 1998-03-31 2000-07-25 Siemens Information And Communication Networks, Inc. Apparatus and method for automated event notification
US6264913B1 (en) 1998-05-08 2001-07-24 Metabolic Solutions, Inc. Non-invasive test for assessing bacterial overgrowth of the small intestine
US6620800B1 (en) 1998-06-29 2003-09-16 Vanderbilt University Methods and compositions to assess oxidative brain injury
EP0979997A1 (fr) 1998-08-12 2000-02-16 Siemens Aktiengesellschaft Methode et dispositif permettant d' identifier du liquide secrete par un vivant, notamment du liquide amniotique
US6153147A (en) 1998-10-06 2000-11-28 Craig; James J. Beverage analysis sample
EP1095255A1 (fr) 1998-10-28 2001-05-02 Douglas F. Copp Procede et appareil de localisation de cadavres caches, par detection de melanges de gaz volatils
US20010055544A1 (en) 1998-10-28 2001-12-27 Douglas Copp Probe arm with multiple detectors for locating disaster and accident victims
US6136801A (en) 1998-12-24 2000-10-24 U. D. Testing, Inc. Therapeutic agent with quantitative consumption marker
DE29902593U1 (de) 1999-02-13 1999-07-15 Genzyme Virotech GmbH, 65428 Rüsselsheim Gasanalysator für die medizinische Diagnostik
US6097485A (en) 1999-03-08 2000-08-01 Integrated Waveguides, Inc. Microchip optical transport technology for use in a personal flow cytometer
US6479019B1 (en) 1999-04-15 2002-11-12 Quantum Group, Inc. Sensor and sensor assembly for detecting a target gas in a breath sample
GB9909308D0 (en) 1999-04-22 1999-06-16 Univ Cambridge Tech Measurement and use of molecular interactions
US6631333B1 (en) 1999-05-10 2003-10-07 California Institute Of Technology Methods for remote characterization of an odor
AU6046700A (en) 1999-05-10 2000-11-21 California Institute Of Technology Use of spatiotemporal response behavior in sensor arrays to detect analytes in fluids
US6277081B1 (en) 1999-05-18 2001-08-21 Invivo Research, Inc. Anesthetic gas detection apparatus
US6656127B1 (en) 1999-06-08 2003-12-02 Oridion Breathid Ltd. Breath test apparatus and methods
CA2375516A1 (fr) 1999-06-17 2000-12-28 Cyrano Sciences, Inc. Systeme et dispositif de detection multiple
CA2379711A1 (fr) 1999-07-02 2001-01-25 Conceptual Mindworks, Inc Systeme et complexe de reconnaissance au moyen de semi-conducteur organique
US6974706B1 (en) 2003-01-16 2005-12-13 University Of Florida Research Foundation, Inc. Application of biosensors for diagnosis and treatment of disease
JP2003521695A (ja) 2000-02-03 2003-07-15 リサーチ ディベロップメント ファンデーション 分子認識を識別信号に変換する情報伝達アプタマー
US6495824B1 (en) 2000-03-13 2002-12-17 Bechtel Bwxt Idaho, Llc Ion mobility spectrometer, spectrometer analyte detection and identification verification system, and method
US6599281B1 (en) 2000-05-03 2003-07-29 Aspect Medical Systems, Inc. System and method for adaptive drug delivery
US6597438B1 (en) 2000-08-02 2003-07-22 Honeywell International Inc. Portable flow cytometry
EP1162453A1 (fr) 2000-06-07 2001-12-12 Asulab S.A. Capteur électrochimique à reproductibilité accrue
US6416479B1 (en) 2000-07-14 2002-07-09 Natus Medical, Inc. Method for using breath carbon monoxide concentration measurements to detect pregnant women at risk for or experiencing various pathological conditions relating to pregnancy
AU2001293226A1 (en) 2000-08-28 2002-03-13 Healthtech, Inc. Respiratory gas sensors in flow path
US7104963B2 (en) 2002-01-22 2006-09-12 University Of Florida Research Foundation, Inc. Method and apparatus for monitoring intravenous (IV) drug concentration using exhaled breath
US6958216B2 (en) 2001-01-10 2005-10-25 The Trustees Of Boston College DNA-bridged carbon nanotube arrays
US6631291B2 (en) 2001-05-18 2003-10-07 Instrumentarium Corp. Closed loop drug administration method and apparatus using EEG complexity for control purposes
US7052854B2 (en) * 2001-05-23 2006-05-30 University Of Florida Research Foundation, Inc. Application of nanotechnology and sensor technologies for ex-vivo diagnostics
AU2002310031A1 (en) 2001-05-23 2002-12-03 University Of Florida Method and apparatus for detecting illicit substances
US6599253B1 (en) * 2001-06-25 2003-07-29 Oak Crest Institute Of Science Non-invasive, miniature, breath monitoring apparatus
KR100455284B1 (ko) 2001-08-14 2004-11-12 삼성전자주식회사 탄소나노튜브를 이용한 고용량의 바이오분자 검출센서
CA2465048A1 (fr) 2001-11-09 2003-05-15 Dow Global Technologies Inc. Systeme a base d'enzymes et capteur servant a detecter l'acetone
US20070167853A1 (en) * 2002-01-22 2007-07-19 Melker Richard J System and method for monitoring health using exhaled breath
US6869591B2 (en) 2002-03-26 2005-03-22 Barnes-Jewish Hospital Paramagnetic particles that provide improved relaxivity
CN1723480A (zh) * 2002-05-13 2006-01-18 斯科特实验室公司 用于医疗过程期间透明的早期检测、警告和干预的系统和方法
WO2004073497A2 (fr) 2003-02-14 2004-09-02 The Charlotte-Mecklenburg Hospital Authority Dispositif et procede de collecte de condensat d'exhalation alveolaire
DE10335236B3 (de) * 2003-08-01 2005-02-24 Drägerwerk AG Messsystem für die Bestimmung der Konzentration von Propofol (2,6-Diisopropylphenol) im Atemstrom

Patent Citations (101)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3567029A (en) * 1969-08-26 1971-03-02 Babington A Quame Column for testing biological fluids
US3649199A (en) * 1970-03-26 1972-03-14 Varian Associates Method for detecting trace quantities of an organic drug material in a living animal
US3955926A (en) * 1972-02-12 1976-05-11 Merck Patent Gesellschaft Mit Beschrankter Haftung Process and quick-action reagent for the detection of narcotics
US3877291A (en) * 1972-08-15 1975-04-15 Borg Warner Portable breath tester
US3792272A (en) * 1973-01-12 1974-02-12 Omicron Syst Corp Breath test device for organic components, including alcohol
US3792272B1 (fr) * 1973-01-12 1986-07-22
US3951607A (en) * 1974-11-29 1976-04-20 Searle Cardio-Pulmonary Systems Inc. Gas analyzer
US4150670A (en) * 1977-11-14 1979-04-24 University Patents, Inc. Anesthesia detector and display apparatus
US4215409A (en) * 1978-03-13 1980-07-29 Mckesson Company Flow control system for anesthesia apparatus
US4202352A (en) * 1978-04-06 1980-05-13 Research Development Corporation Apparatus for measurement of expired gas concentration in infants
US4314564A (en) * 1979-02-22 1982-02-09 Dragerwerk Aktiengesellschaft Method and apparatus for determining alcohol concentration in the blood
US4334540A (en) * 1979-05-01 1982-06-15 Monell Chemical Senses Center Method of diagnosing periodontal disease through the detection of pyridine compounds
US4312228A (en) * 1979-07-30 1982-01-26 Henry Wohltjen Methods of detection with surface acoustic wave and apparati therefor
US4432226A (en) * 1982-02-05 1984-02-21 Dempster Philip T Method and apparatus for measuring gaseous oxygen
US4734777A (en) * 1982-12-07 1988-03-29 Canon Kabushiki Kaisha Image pick-up apparatus having an exposure control device
US4456014A (en) * 1983-01-03 1984-06-26 Thoratec Laboratories Corporation Flow restrictor
US5034192A (en) * 1984-11-23 1991-07-23 Massachusetts Institute Of Technology Molecule-based microelectronic devices
US4735777A (en) * 1985-03-11 1988-04-05 Hitachi, Ltd. Instrument for parallel analysis of metabolites in human urine and expired air
US4938928A (en) * 1986-10-28 1990-07-03 Figaro Engineering Inc. Gas sensor
US4796639A (en) * 1987-11-05 1989-01-10 Medical Graphics Corporation Pulmonary diagnostic system
US5003985A (en) * 1987-12-18 1991-04-02 Nippon Colin Co., Ltd. End tidal respiratory monitor
US5111827A (en) * 1988-02-11 1992-05-12 Instrumentarium Corp. Respiratory sampling device
US4992244A (en) * 1988-09-27 1991-02-12 The United States Of America As Represented By The Secretary Of The Navy Films of dithiolene complexes in gas-detecting microsensors
US4895017A (en) * 1989-01-23 1990-01-23 The Boeing Company Apparatus and method for early detection and identification of dilute chemical vapors
US5317506A (en) * 1989-01-30 1994-05-31 Abbott Laboratories Infusion fluid management system
US5081871A (en) * 1989-02-02 1992-01-21 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Breath sampler
US5094235A (en) * 1989-05-10 1992-03-10 Dragerwerk Aktiengesellschaft Anesthesia ventilating apparatus having a breathing circuit and control loops for anesthetic gas components
US5231591A (en) * 1989-09-11 1993-07-27 Nellcor Incorporated Agent gas analyzer and method of use
US5082630A (en) * 1990-04-30 1992-01-21 The United States Of America As Represented By The United States Department Of Energy Fiber optic detector for immuno-testing
US5179027A (en) * 1991-01-10 1993-01-12 Fisher Murray M Method employing chemical markers and kit for verifying the source and completeness of urine samples for testing for the presence of drugs of abuse
US5501212A (en) * 1991-09-25 1996-03-26 Siemens Aktiengesellschaft In-line dehumidifying device exposed to the ambient environment
US5317156A (en) * 1992-01-29 1994-05-31 Sri International Diagnostic tests using near-infrared laser absorption spectroscopy
US5425374A (en) * 1992-06-03 1995-06-20 Hideo Ueda Device and method for expiratory air examination
US5296706A (en) * 1992-12-02 1994-03-22 Critikon, Inc. Shutterless mainstream discriminating anesthetic agent analyzer
US5303575A (en) * 1993-06-01 1994-04-19 Alcotech Research Inc. Apparatus and method for conducting an unsupervised blood alcohol content level test
US5918257A (en) * 1993-09-17 1999-06-29 Alpha M.O.S. Methods and devices for the detection of odorous substances and applications
US5495744A (en) * 1993-10-25 1996-03-05 Kyoto Dai-Ichi Kagaku Co., Ltd. Method of correcting componential concentration in expiration and expiration analyzer
US5409839A (en) * 1993-11-01 1995-04-25 International Electronic Technology Corp. Method of tagging and detecting drugs, crops, chemical compounds and currency with perfluorocarbon tracers (PFT'S)
US5605612A (en) * 1993-11-11 1997-02-25 Goldstar Electron Co., Ltd. Gas sensor and manufacturing method of the same
US5528924A (en) * 1993-11-29 1996-06-25 Leybold Inficon Inc. Acoustic tool for analysis of a gaseous substance
US5634517A (en) * 1994-01-27 1997-06-03 Siemens-Elema Ab Device for reducing the relative humidity of a flowing gas
US5482601A (en) * 1994-01-28 1996-01-09 Director-General Of Agency Of Industrial Science And Technology Method and device for the production of carbon nanotubes
US5771890A (en) * 1994-06-24 1998-06-30 Cygnus, Inc. Device and method for sampling of substances using alternating polarity
US5866434A (en) * 1994-12-08 1999-02-02 Meso Scale Technology Graphitic nanotubes in luminescence assays
US6203814B1 (en) * 1994-12-08 2001-03-20 Hyperion Catalysis International, Inc. Method of making functionalized nanotubes
US6251082B1 (en) * 1995-02-06 2001-06-26 Ntc Technology, Inc. Non-invasive estimation of arterial blood gases
US6063243A (en) * 1995-02-14 2000-05-16 The Regents Of The Univeristy Of California Method for making nanotubes and nanoparticles
US5891398A (en) * 1995-03-27 1999-04-06 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US5716852A (en) * 1996-03-29 1998-02-10 University Of Washington Microfabricated diffusion-based chemical sensor
US6010459A (en) * 1996-04-09 2000-01-04 Silkoff; Philip E. Method and apparatus for the measurement of components of exhaled breath in humans
US7335164B2 (en) * 1996-07-15 2008-02-26 Ntc Technology, Inc. Multiple function airway adapter
US5756879A (en) * 1996-07-25 1998-05-26 Hughes Electronics Volatile organic compound sensors
US6341520B1 (en) * 1996-08-13 2002-01-29 Suzuki Motor Corporation Method and apparatus for analyzing breath sample
US6025200A (en) * 1996-12-21 2000-02-15 Tracer Detection Technology Corp. Method for remote detection of volatile taggant
US6190858B1 (en) * 1997-01-02 2001-02-20 Osmetech Plc Detection of conditions by analysis of gases or vapors
US6180414B1 (en) * 1997-01-03 2001-01-30 Oridion Medical Ltd. Breath test for detection of drug metabolism
US5861254A (en) * 1997-01-31 1999-01-19 Nexstar Pharmaceuticals, Inc. Flow cell SELEX
US6057162A (en) * 1997-03-07 2000-05-02 Thermedics Detection, Inc. Disease diagnosis by vapor sample analysis
US6511453B2 (en) * 1997-03-10 2003-01-28 Michael Georgieff Device for controlled anaesthesia, analgesia and/or sedation
US5900552A (en) * 1997-03-28 1999-05-04 Ohmeda Inc. Inwardly directed wave mode ultrasonic transducer, gas analyzer, and method of use and manufacture
US6186977B1 (en) * 1997-04-24 2001-02-13 Joseph L. Riley Anesthesia Associates Apparatus and method for total intravenous anesthesia delivery and associated patient monitoring
USRE38728E1 (en) * 1997-09-11 2005-04-19 Oridion Medical, LTD Breath test analyzer
US6216690B1 (en) * 1997-10-15 2001-04-17 Datex-Ohmeda, Inc. Method and apparatus for rapid control of set inspired gas concentration in anesthesia delivery systems
US20030059820A1 (en) * 1997-11-26 2003-03-27 Tuan Vo-Dinh SERS diagnostic platforms, methods and systems microarrays, biosensors and biochips
US6234006B1 (en) * 1998-03-20 2001-05-22 Cyrano Sciences Inc. Handheld sensing apparatus
US20020034757A1 (en) * 1998-05-20 2002-03-21 Cubicciotti Roger S. Single-molecule selection methods and compositions therefrom
US6807965B1 (en) * 1998-06-03 2004-10-26 Scott Laboratories, Inc. Apparatus and method for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures
US6244096B1 (en) * 1998-06-19 2001-06-12 California Institute Of Technology Trace level detection of analytes using artificial olfactometry
US6371114B1 (en) * 1998-07-24 2002-04-16 Minnesota Innovative Technologies & Instruments Corporation Control device for supplying supplemental respiratory oxygen
US6067167A (en) * 1998-08-10 2000-05-23 Innovative Lasers Corp. ILS sensors for drug detection within vehicles
US6399302B1 (en) * 1998-08-21 2002-06-04 University Of Virginia Patent Foundation Signal generating oligonucleotide-based biosensor
US6248078B1 (en) * 1998-08-31 2001-06-19 Johns Hopkins University Volatile biomarkers for analysis of hepatic disorders
US6074345A (en) * 1998-10-27 2000-06-13 University Of Florida Patient data acquisition and control system
US6387329B1 (en) * 1998-11-16 2002-05-14 California Institute Of Technology Use of an array of polymeric sensors of varying thickness for detecting analytes in fluids
US6727075B2 (en) * 1998-12-02 2004-04-27 The Trustees Of The University Of Pennsylvania Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases
US6221026B1 (en) * 1999-01-12 2001-04-24 Michael Phillips Breath test for the detection of various diseases
US20020007687A1 (en) * 1999-03-24 2002-01-24 Ralf Zimmermann Method for detecting trace substances and/or environmental properties
US6755783B2 (en) * 1999-04-16 2004-06-29 Cardiocom Apparatus and method for two-way communication in a device for monitoring and communicating wellness parameters of ambulatory patients
US6680377B1 (en) * 1999-05-14 2004-01-20 Brandeis University Nucleic acid-based detection
US6237397B1 (en) * 1999-10-06 2001-05-29 Iowa State University Research Foundation, Inc. Chemical sensor and coating for same
US20050037374A1 (en) * 1999-11-08 2005-02-17 Melker Richard J. Combined nanotechnology and sensor technologies for simultaneous diagnosis and treatment
US6363772B1 (en) * 1999-12-10 2002-04-02 Quadrivium, L.L.C. System and method for detection of a biological condition
US20020007249A1 (en) * 2000-02-22 2002-01-17 Cranley Paul E. Personal computer breath analyzer for health-related behavior modification and method
US20020014236A1 (en) * 2000-03-25 2002-02-07 Ralf Dittmann Arrangement and process for controlling a numerical value for patient respiration
US20020017300A1 (en) * 2000-06-13 2002-02-14 Hickle Randall S. Apparatus and method for mask free delivery of an inspired gas mixture and gas sampling
US20020068295A1 (en) * 2000-07-13 2002-06-06 Marc Madou Multimeric biopolymers as structural elements and sensors and actuators in microsystems
US20020026937A1 (en) * 2000-08-28 2002-03-07 Mault James R. Respiratory gas sensors in folw path
US20040038386A1 (en) * 2000-09-04 2004-02-26 Wolfgang Zesch Multianalyte determination system and methods
US20030087239A1 (en) * 2000-09-13 2003-05-08 Marty Stanton Target activated nucleic acid biosensor and methods of using same
US6558626B1 (en) * 2000-10-17 2003-05-06 Nomadics, Inc. Vapor sensing instrument for ultra trace chemical detection
US20030008407A1 (en) * 2001-03-03 2003-01-09 Fu Chi Yung Non-invasive diagnostic and monitoring system based on odor detection
US20030004426A1 (en) * 2001-05-24 2003-01-02 Melker Richard J. Method and apparatus for detecting environmental smoke exposure
US20030023180A1 (en) * 2001-07-26 2003-01-30 Mault James R. Respiratory analyzer and method for measuring changes in concentration of a gas component of a breathing gas mixture
US20030119065A1 (en) * 2001-12-21 2003-06-26 Industrial Technology Research Institute Peptide and amine examination method using the same
US20050054942A1 (en) * 2002-01-22 2005-03-10 Melker Richard J. System and method for therapeutic drug monitoring
US6981947B2 (en) * 2002-01-22 2006-01-03 University Of Florida Research Foundation, Inc. Method and apparatus for monitoring respiratory gases during anesthesia
US20050065446A1 (en) * 2002-01-29 2005-03-24 Talton James D Methods of collecting and analyzing human breath
US20070062255A1 (en) * 2002-01-29 2007-03-22 Nanotherapeutics, Inc. Apparatus for collecting and analyzing human breath
US20050083527A1 (en) * 2002-07-23 2005-04-21 Bryan Flaherty Disposable sensor for use in measuring an analyte in a gaseous sample
US20040027246A1 (en) * 2002-08-09 2004-02-12 S.I.E.M. S.R.L. Portable device with sensors for signalling physiological data
US20040101477A1 (en) * 2002-11-27 2004-05-27 Xanthus Life Sciences, Inc. Individualization of therapy with anesthetics

Cited By (182)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8211035B2 (en) * 2002-01-22 2012-07-03 University Of Florida Research Foundation, Inc. System and method for monitoring health using exhaled breath
US20120016252A1 (en) * 2002-01-22 2012-01-19 Melker Richard J System and method for monitoring health using exhaled breath
US8272411B2 (en) 2003-04-28 2012-09-25 Medical Instill Technologies, Inc. Lyophilization method and device
US20100154245A1 (en) * 2003-04-28 2010-06-24 Daniel Py Lyophilization method and device
US9936897B2 (en) 2003-06-19 2018-04-10 Capnia, Inc. Breath end-tidal gas monitor
US20110224950A1 (en) * 2003-12-31 2011-09-15 Sieracki Jeffrey M Indirect Monitoring of Device Usage and Activities
US8407028B2 (en) * 2003-12-31 2013-03-26 Jeffrey M. Sieracki Indirect monitoring of device usage and activities
US20070287359A1 (en) * 2004-02-26 2007-12-13 Pixen Inc. Diagnostic Sensor
US20080091116A1 (en) * 2004-03-31 2008-04-17 Mats Cardell Arrangement for Analysing Respiratory Gases
US7594894B2 (en) * 2004-03-31 2009-09-29 Artema Medical Ab Arrangement for analysing respiratory gases
US20110270053A1 (en) * 2004-05-28 2011-11-03 David Scott Utley Intra-Oral Detector and System for Modification of Undesired Behaviors and Methods Thereof
US20090012216A1 (en) * 2006-03-15 2009-01-08 Toshiyuki Yamauchi Stabilized Polyolefin-Based Resin and Polyolefin-Based Resin Stabilization Process
US8171652B2 (en) 2006-04-24 2012-05-08 Medical Instill Technologies, Inc. Penetrable and resealable lyophilization method
US9222728B2 (en) 2006-04-24 2015-12-29 Medinstill Development Llc Penetrable and resealable lyophilization device
US7966746B2 (en) * 2006-04-24 2011-06-28 Medical Instill Technologies, LLC Needle penetrable and laser resealable lyophilization method
US20080039773A1 (en) * 2006-04-24 2008-02-14 Daniel Py Needle penetrable and laser resealable lyophilization device and related method
US20080028632A1 (en) * 2006-04-24 2008-02-07 Daniel Py Needle penetrable and laser resealable lyophilization device and related method
US20090032695A1 (en) * 2006-06-09 2009-02-05 Kaye William J Miniaturized Ion Mobility Spectrometer
US8963082B2 (en) * 2006-06-09 2015-02-24 Rapiscan Systems, Inc. Miniaturized ion mobility spectrometer
US20150303044A1 (en) * 2006-06-09 2015-10-22 Rapiscan Systems, Inc. Miniaturized Ion Mobility Spectrometer
US9646811B2 (en) * 2006-06-09 2017-05-09 Rapiscan Systems, Inc. Miniaturized ion mobility spectrometer
US20080045825A1 (en) * 2006-08-15 2008-02-21 Melker Richard J Condensate glucose analyzer
US7914460B2 (en) * 2006-08-15 2011-03-29 University Of Florida Research Foundation, Inc. Condensate glucose analyzer
US20100216175A1 (en) * 2006-08-15 2010-08-26 Melker Richard J Condensate Glucose Analyzer
WO2009018207A1 (fr) * 2007-07-27 2009-02-05 Ned, Llc Procédé de traitement d'une dépression post-partum et d'une agression
US20090028800A1 (en) * 2007-07-27 2009-01-29 Peeples William H Method of Treating Postpartum Depression and Aggression
US9976944B2 (en) * 2007-10-02 2018-05-22 Pexa Ab Collection and measurement of exhaled particles
US20100297635A1 (en) * 2007-10-02 2010-11-25 Anna-Carin Olin Collection and measurement of exhaled particles
US8418523B2 (en) 2008-03-03 2013-04-16 Keith Lueck Calibration and accuracy check system for a breath tester
US8713985B2 (en) 2008-03-03 2014-05-06 Alcotek, Inc. Calibration and accuracy check system
US20090312668A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20090271219A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The Stste Of Delaware Methods and systems for presenting a combination treatment
US20100042578A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100041964A1 (en) * 2008-04-24 2010-02-18 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20100041958A1 (en) * 2008-04-24 2010-02-18 Searete Llc Computational system and method for memory modification
US20090271375A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20100063368A1 (en) * 2008-04-24 2010-03-11 Searete Llc, A Limited Liability Corporation Computational system and method for memory modification
US20100069724A1 (en) * 2008-04-24 2010-03-18 Searete Llc Computational system and method for memory modification
US20100076249A1 (en) * 2008-04-24 2010-03-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100081860A1 (en) * 2008-04-24 2010-04-01 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US20100100036A1 (en) * 2008-04-24 2010-04-22 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational System and Method for Memory Modification
US9662391B2 (en) 2008-04-24 2017-05-30 The Invention Science Fund I Llc Side effect ameliorating combination therapeutic products and systems
US20100125561A1 (en) * 2008-04-24 2010-05-20 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100130811A1 (en) * 2008-04-24 2010-05-27 Searete Llc Computational system and method for memory modification
US20100017001A1 (en) * 2008-04-24 2010-01-21 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US20100004762A1 (en) * 2008-04-24 2010-01-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US9649469B2 (en) 2008-04-24 2017-05-16 The Invention Science Fund I Llc Methods and systems for presenting a combination treatment
US20090271122A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US9560967B2 (en) 2008-04-24 2017-02-07 The Invention Science Fund I Llc Systems and apparatus for measuring a bioactive agent effect
US20100280332A1 (en) * 2008-04-24 2010-11-04 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US20090319301A1 (en) * 2008-04-24 2009-12-24 Searete Llc, A Limited Liability Corporation Of The State Of Delawar Methods and systems for presenting a combination treatment
US9504788B2 (en) 2008-04-24 2016-11-29 Searete Llc Methods and systems for modifying bioactive agent use
US9449150B2 (en) 2008-04-24 2016-09-20 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US20090271009A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment modification methods and systems
US20090312595A1 (en) * 2008-04-24 2009-12-17 Searete Llc, A Limited Liability Corporation Of The State Of Delaware System and method for memory modification
US20090292676A1 (en) * 2008-04-24 2009-11-26 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment selection methods and systems
US20090271011A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US9358361B2 (en) 2008-04-24 2016-06-07 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US20090271347A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring bioactive agent use
US9282927B2 (en) 2008-04-24 2016-03-15 Invention Science Fund I, Llc Methods and systems for modifying bioactive agent use
US20090270693A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for modifying bioactive agent use
US9239906B2 (en) 2008-04-24 2016-01-19 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US20090267758A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems and apparatus for measuring a bioactive agent effect
US20090270688A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for presenting a combination treatment
US20100022820A1 (en) * 2008-04-24 2010-01-28 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational system and method for memory modification
US10572629B2 (en) 2008-04-24 2020-02-25 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US20090270694A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for monitoring and modifying a combination treatment
US20090271213A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Corporation Of The State Of Delaware Combination treatment selection methods and systems
US9064036B2 (en) * 2008-04-24 2015-06-23 The Invention Science Fund I, Llc Methods and systems for monitoring bioactive agent use
US10786626B2 (en) 2008-04-24 2020-09-29 The Invention Science Fund I, Llc Methods and systems for modifying bioactive agent use
US9026369B2 (en) 2008-04-24 2015-05-05 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US20090271215A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Methods and systems for detecting a bioactive agent effect
US20090271008A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination treatment modification methods and systems
US20090269329A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Combination Therapeutic products and systems
US8930208B2 (en) 2008-04-24 2015-01-06 The Invention Science Fund I, Llc Methods and systems for detecting a bioactive agent effect
US8876688B2 (en) 2008-04-24 2014-11-04 The Invention Science Fund I, Llc Combination treatment modification methods and systems
US20090271217A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Side effect ameliorating combination therapeutic products and systems
US20100050744A1 (en) * 2008-08-26 2010-03-04 Honeywell International Inc. Multi-sensor Gas Detectors
US8186201B2 (en) * 2008-08-26 2012-05-29 Honeywell International Inc. Multi-sensor gas detectors
US9121844B1 (en) * 2008-09-09 2015-09-01 Sociedad Europea de Analisis Diferencial de Movilidad Method to analyze and classify persons and organisms based on odor patterns from released vapors
US8978651B2 (en) * 2008-10-28 2015-03-17 General Electric Company Anesthesia system and method
US20100101571A1 (en) * 2008-10-28 2010-04-29 General Electric Company Anesthesia system and method
US20100241019A1 (en) * 2009-03-18 2010-09-23 Cardinal Health 207, Inc. Exhaled breath condensate biometric marker measurement apparatus and method
US8394030B2 (en) * 2009-03-18 2013-03-12 Carefusion 207, Inc. Exhaled breath condensate biometric marker measurement apparatus and method
US20100268106A1 (en) * 2009-04-15 2010-10-21 Nanomix, Inc. Breath condensate sampler and detector and breath/breath condensate sampler and detector
CN102803943A (zh) * 2009-04-15 2012-11-28 纳诺米克斯公司 呼吸冷凝液取样器和检测器以及呼吸/呼吸冷凝液取样器和检测器
US9357946B2 (en) * 2009-04-15 2016-06-07 Nanomix, Inc. Breath condensate sampler and detector and breath/breath condensate sampler and detector
WO2010121072A1 (fr) * 2009-04-15 2010-10-21 Nanomix, Inc. Détecteur et analyseur d'haleine et analyseur/détecteur d'haleine combiné
JP2012524267A (ja) * 2009-04-15 2012-10-11 ナノミックス・インコーポレーテッド 呼気のサンプリングと検出用の携帯型ユニット、及び、呼気の中の分析物を検出する方法
CN102803943B (zh) * 2009-04-15 2016-03-16 纳诺米克斯公司 呼吸冷凝液取样器和检测器以及呼吸/呼吸冷凝液取样器和检测器
US9532731B2 (en) * 2009-10-22 2017-01-03 Koninklijke Philips N.V. Method and apparatus for measuring the concentration of a gas in exhaled air
US20120203126A1 (en) * 2009-10-22 2012-08-09 Koninklijke Philips Electronics N.V. Method and apparatus for measuring the concentration of a gas in exhaled air
US20110098590A1 (en) * 2009-10-26 2011-04-28 Pulse Health Llc Methods and apparatuses for detecting analytes
US20110105856A1 (en) * 2009-10-29 2011-05-05 Robyn Aylor Haines Diagnostic testing
US11000667B2 (en) * 2009-11-16 2021-05-11 Maquet Critical Care Ab Breathing apparatus with monitored delivery device
US20160151601A1 (en) * 2009-11-16 2016-06-02 Maquet Critical Care Ab Breathing apparatus with monitored delivery device
CN103097891A (zh) * 2010-05-31 2013-05-08 国立大学法人德岛大学 疾病重症度的检查方法
US20110313306A1 (en) * 2010-06-16 2011-12-22 Sociedad Europea de Analisis Diferencial de Movilidad Method and apparatus for monitoring stress levels or sudden changes of humor in humans or other individuals in real time by means of vapor analysis
KR101119594B1 (ko) * 2010-08-13 2012-03-06 경북대학교 산학협력단 폐질환 환자의 호기측정 시스템 및 방법
US20120136269A1 (en) * 2010-11-26 2012-05-31 Kurt Peter Weckstrom Liquid separation apparatus for removing a liquid from a respiratory gas and respiratory gas analyzing system
US20120183949A1 (en) * 2011-01-19 2012-07-19 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Method, device, or system using lung sensor for detecting a physiological condition in a vertebrate subject
US8844337B2 (en) * 2011-04-29 2014-09-30 Theodosios Kountotsis Breath actuation of electronic and non-electronic devices for preventing unauthorized access
US9830441B2 (en) * 2011-04-29 2017-11-28 Theodosios Kountotsis Breath actuation of electronic and non-electronic devices for preventing unauthorized access
US20120272713A1 (en) * 2011-04-29 2012-11-01 Theodosios Kountotsis Breath actuation of electronic and non-electronic devices for preventing unauthorized access
US20140366126A1 (en) * 2011-04-29 2014-12-11 Theodosios Kountotsis Breath actuation of electronic and non-electronic devices for preventing unauthorized access
US11691165B2 (en) 2011-10-27 2023-07-04 Copilot Ventures Fund Iii Llc Methods of delivery of encapsulated perfluorocarbon taggants
US9953818B2 (en) * 2011-11-17 2018-04-24 Owlstone Medical Limited Sensor apparatus and method for use with gas ionization systems
US20170004958A1 (en) * 2011-11-17 2017-01-05 Ownstone Medical Limited Sensor apparatus and method for use with gas ionization systems
US10034621B2 (en) 2011-12-21 2018-07-31 Capnia, Inc. Collection and analysis of a volume of exhaled gas with compensation for the frequency of a breathing parameter
US9089279B2 (en) * 2011-12-29 2015-07-28 General Electric Company Ion-based breath analysis system
US20130168548A1 (en) * 2011-12-29 2013-07-04 General Electric Company Ion-based breath analysis system
US9125590B2 (en) * 2012-02-01 2015-09-08 National Tsing Hua University Medical ventilator capable of early detecting and recognizing types of pneumonia, gas recognition chip, and method for recognizing gas thereof
US20130197384A1 (en) * 2012-02-01 2013-08-01 National Tsing Hua University Medical Ventilator Capable of Early Detecting and Recognizing Types of Pneumonia, Gas Recognition Chip, and Method for Recognizing Gas Thereof
US20150038940A1 (en) * 2012-03-13 2015-02-05 Universitaet Des Saarlandes Appliance for performing anaesthesia or analgosedation, and method for operating an appliance for performing anaesthesia or analgosedation
US10806879B2 (en) 2012-04-27 2020-10-20 Covidien Lp Methods and systems for an optimized proportional assist ventilation
US9993604B2 (en) 2012-04-27 2018-06-12 Covidien Lp Methods and systems for an optimized proportional assist ventilation
US11642042B2 (en) 2012-07-09 2023-05-09 Covidien Lp Systems and methods for missed breath detection and indication
US10362967B2 (en) 2012-07-09 2019-07-30 Covidien Lp Systems and methods for missed breath detection and indication
US9027552B2 (en) 2012-07-31 2015-05-12 Covidien Lp Ventilator-initiated prompt or setting regarding detection of asynchrony during ventilation
US10499819B2 (en) 2013-01-08 2019-12-10 Capnia, Inc. Breath selection for analysis
US11331004B2 (en) 2013-02-12 2022-05-17 Capnia, Inc. Sampling and storage registry device for breath gas analysis
US11749394B2 (en) 2013-06-20 2023-09-05 Takeda Pharmaceutical Company Limited Method and apparatus for providing a pharmacokinetic drug dosing regimen
US11081211B2 (en) 2013-06-20 2021-08-03 Baxalta Incorporated Method and apparatus for providing a pharmacokinetic drug dosing regimen
US11191449B2 (en) 2013-08-30 2021-12-07 Capnia, Inc. Neonatal carbon dioxide measurement system
US20150265184A1 (en) * 2014-03-20 2015-09-24 Capnia, Inc. Selection, segmentation and analysis of exhaled breath for airway disorders assessment
WO2015191579A1 (fr) * 2014-06-11 2015-12-17 Integrated Monitoring Systems, Llc Système d'échantillonnage d'alcool respiratoire inviolable amovible
US9696294B2 (en) 2014-06-11 2017-07-04 Integrated Monitoring Systems, Llc Removable tamper-resistant breath alcohol sampling system
US11262354B2 (en) 2014-10-20 2022-03-01 Boston Scientific Scimed, Inc. Disposable sensor elements, systems, and related methods
US11712174B2 (en) 2014-10-27 2023-08-01 Covidien Lp Ventilation triggering
US9950129B2 (en) 2014-10-27 2018-04-24 Covidien Lp Ventilation triggering using change-point detection
US10940281B2 (en) 2014-10-27 2021-03-09 Covidien Lp Ventilation triggering
US20160158471A1 (en) * 2014-12-05 2016-06-09 Dance Biopharm, Inc. Integration of glucose data to adjust inhaled insulin dose
US10702208B2 (en) * 2015-03-31 2020-07-07 Cerenion Oy Apparatus and method for electroencephalographic examination
US20160287169A1 (en) * 2015-03-31 2016-10-06 Oulun Yliopisto Apparatus and method for electroencephalographic examination
CN108603871A (zh) * 2015-10-29 2018-09-28 英福康有限责任公司 使用气体调制的气体检测
US10352848B2 (en) * 2015-10-29 2019-07-16 Inficon Gmbh Gas detection using gas modulation
WO2017140865A1 (fr) * 2016-02-19 2017-08-24 Patonomics Ab Procédé et appareil permettant d'identifier un état émotionnel transitoire d'un mammifère vivant
EP3207868A1 (fr) * 2016-02-19 2017-08-23 Patonomics AB Procédé et appareil permettant d'identifier un état émotionnel transitoire d'un mammifère vivant
US11103159B2 (en) * 2016-03-04 2021-08-31 United States Of America As Represented By The Secretary Of The Air Force Exhaled breath hypoxia biomarkers
US20210307644A1 (en) * 2016-03-04 2021-10-07 Government Of The United States As Represented By The Secretary Of The Air Force Exhaled breath hypoxia biomarkers
US11813051B2 (en) * 2016-03-04 2023-11-14 United States Of America As Represented By The Secretary Of The Air Force Exhaled breath hypoxia biomarkers
US20170251952A1 (en) * 2016-03-04 2017-09-07 Government Of The United States As Represented By The Secretary Of The Air Force Exhaled breath hypoxia biomarkers
US11670409B2 (en) 2016-04-15 2023-06-06 Takeda Pharmaceutical Company Limited Method and apparatus for providing a pharmacokinetic drug dosing regiment
US11191457B2 (en) 2016-06-15 2021-12-07 Boston Scientific Scimed, Inc. Gas sampling catheters, systems and methods
US11172846B2 (en) 2016-10-21 2021-11-16 Boston Scientific Scimed, Inc. Gas sampling device
KR20180060469A (ko) * 2016-11-29 2018-06-07 한국기계연구원 단일 호흡기체의 분석방법과 분석장치
WO2018101650A1 (fr) * 2016-11-29 2018-06-07 한국기계연구원 Procédé d'analyse et appareil d'analyse d'un gaz en une seule respiration
US10896749B2 (en) 2017-01-27 2021-01-19 Shire Human Genetic Therapies, Inc. Drug monitoring tool
US11783931B2 (en) 2017-01-27 2023-10-10 Takeda Pharmaceutical Company Limited Drug monitoring tool
WO2018144373A1 (fr) * 2017-02-01 2018-08-09 Shire Human Genetic Therapies, Inc. Système et procédé de détection physiologique et d'administration d'un agent thérapeutique
US10770182B2 (en) 2017-05-19 2020-09-08 Boston Scientific Scimed, Inc. Systems and methods for assessing the health status of a patient
US11714058B2 (en) 2017-07-18 2023-08-01 Regents Of The University Of Minnesota Systems and methods for analyte sensing in physiological gas samples
US10852264B2 (en) 2017-07-18 2020-12-01 Boston Scientific Scimed, Inc. Systems and methods for analyte sensing in physiological gas samples
US11723579B2 (en) 2017-09-19 2023-08-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement
US11585750B2 (en) * 2017-11-06 2023-02-21 Henkel Ag & Co. Kgaa Arrangement for determining body surface properties by means of Multiple Spatially Resolved Reflection Spectroscopy (MSRRS)
CN109813891A (zh) * 2017-11-18 2019-05-28 镇江亿特生物科技发展有限公司 一种检测氯丙嗪的时间分辨荧光免疫层析定量检测试纸条
US11717686B2 (en) 2017-12-04 2023-08-08 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to facilitate learning and performance
US11273283B2 (en) 2017-12-31 2022-03-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11478603B2 (en) 2017-12-31 2022-10-25 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11318277B2 (en) 2017-12-31 2022-05-03 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11166636B2 (en) 2018-02-20 2021-11-09 Boston Scientific Scimed, Inc. Breath sampling mask and system
US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
US11452839B2 (en) 2018-09-14 2022-09-27 Neuroenhancement Lab, LLC System and method of improving sleep
US12007385B2 (en) 2018-10-19 2024-06-11 Regents Of The University Of Minnesota Systems and methods for detecting a brain condition
US11442056B2 (en) 2018-10-19 2022-09-13 Regents Of The University Of Minnesota Systems and methods for detecting a brain condition
CN109330598A (zh) * 2018-10-31 2019-02-15 上海健康医学院 一种基于符合探测原理的正电子核素实时计数检测仪
US11835435B2 (en) 2018-11-27 2023-12-05 Regents Of The University Of Minnesota Systems and methods for detecting a health condition
US20220034764A1 (en) * 2018-12-03 2022-02-03 Mallinckrodt Hospital Products IP Unlimited Company Gas sensor module
US11662325B2 (en) 2018-12-18 2023-05-30 Regents Of The University Of Minnesota Systems and methods for measuring kinetic response of chemical sensor elements
US11918344B2 (en) * 2019-03-31 2024-03-05 Resmed Inc. Methods and apparatuses for analyzing one or more analytes from a user
US11786694B2 (en) 2019-05-24 2023-10-17 NeuroLight, Inc. Device, method, and app for facilitating sleep
US11324954B2 (en) 2019-06-28 2022-05-10 Covidien Lp Achieving smooth breathing by modified bilateral phrenic nerve pacing
US11921096B2 (en) 2019-09-10 2024-03-05 Regents Of The University Of Minnesota Fluid analysis system
US11760170B2 (en) 2020-08-20 2023-09-19 Denso International America, Inc. Olfaction sensor preservation systems and methods
US11828210B2 (en) 2020-08-20 2023-11-28 Denso International America, Inc. Diagnostic systems and methods of vehicles using olfaction
US11881093B2 (en) 2020-08-20 2024-01-23 Denso International America, Inc. Systems and methods for identifying smoking in vehicles
US11813926B2 (en) 2020-08-20 2023-11-14 Denso International America, Inc. Binding agent and olfaction sensor
US11760169B2 (en) 2020-08-20 2023-09-19 Denso International America, Inc. Particulate control systems and methods for olfaction sensors
US11932080B2 (en) 2020-08-20 2024-03-19 Denso International America, Inc. Diagnostic and recirculation control systems and methods
US11636870B2 (en) 2020-08-20 2023-04-25 Denso International America, Inc. Smoking cessation systems and methods
US12017506B2 (en) 2021-03-31 2024-06-25 Denso International America, Inc. Passenger cabin air control systems and methods
WO2023240832A1 (fr) * 2022-06-14 2023-12-21 惠雨恩科技(深圳)有限公司 Dispositif d'acquisition d'expiration finale

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US8211035B2 (en) 2012-07-03
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