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WO2025024778A1 - Système et méthodes de traitement médical - Google Patents

Système et méthodes de traitement médical Download PDF

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Publication number
WO2025024778A1
WO2025024778A1 PCT/US2024/039768 US2024039768W WO2025024778A1 WO 2025024778 A1 WO2025024778 A1 WO 2025024778A1 US 2024039768 W US2024039768 W US 2024039768W WO 2025024778 A1 WO2025024778 A1 WO 2025024778A1
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WO
WIPO (PCT)
Prior art keywords
lung
active compound
measurements
subject
dose
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/US2024/039768
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English (en)
Inventor
David H. Ingbar
Timothy P. Rich
Robert J. Schumacher
Daniel B. Mckenna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Minnesota Twin Cities
University of Minnesota System
Original Assignee
University of Minnesota Twin Cities
University of Minnesota System
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Publication of WO2025024778A1 publication Critical patent/WO2025024778A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/021—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes operated by electrical means
    • A61M16/022—Control means therefor
    • A61M16/024—Control means therefor including calculation means, e.g. using a processor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/14—Preparation of respiratory gases or vapours by mixing different fluids, one of them being in a liquid phase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
    • G06N20/00—Machine learning
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/1005—Preparation of respiratory gases or vapours with O2 features or with parameter measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/1005—Preparation of respiratory gases or vapours with O2 features or with parameter measurement
    • A61M2016/102—Measuring a parameter of the content of the delivered gas
    • A61M2016/1025—Measuring a parameter of the content of the delivered gas the O2 concentration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/50—General characteristics of the apparatus with microprocessors or computers
    • A61M2205/502—User interfaces, e.g. screens or keyboards
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/581—Means for facilitating use, e.g. by people with impaired vision by audible feedback
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/582—Means for facilitating use, e.g. by people with impaired vision by tactile feedback
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/58—Means for facilitating use, e.g. by people with impaired vision
    • A61M2205/583—Means for facilitating use, e.g. by people with impaired vision by visual feedback
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/20—Blood composition characteristics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/20—Blood composition characteristics
    • A61M2230/202—Blood composition characteristics partial carbon oxide pressure, e.g. partial dioxide pressure (P-CO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/20—Blood composition characteristics
    • A61M2230/205—Blood composition characteristics partial oxygen pressure (P-O2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/30—Blood pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/40—Respiratory characteristics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • this disclosure describes a method of treating a condition in a subject.
  • the method includes measuring a baseline blood level of a lung active compound in a subject, administering an initial dose of lung active compound directly to a portion of the subject’s sinopulmonary tract via a drug dispenser, then via a controller: receiving subsequent blood lung active compound measurements after an initial interval of time, facilitating provision of adjusted dosages of lung active compound to the subject via the drug dispenser, responsive to the adjusted dosages of lung active compound, determining that the lung active compound measurements reach an inflection point that indicates efficacy of the adjusted dosages of lung active compound, and after the efficacy is indicated, facilitating administration of a titrated dosage of lung active compound.
  • the lung active compound is a thyroid hormone.
  • the thyroid hormone is triiodothyronine (T3).
  • the condition being treated includes acute respiratory distress syndrome (ARDS), Heart Failure (HF), infant respiratory distress syndrome (IRDS), or myocardial infarction (MI), acute coronary syndrome (ACS), congenital heart disease, structural heart disease, premature birth, chest trauma, pre lung transplant, post lung transplant, ex vivo perfusion, lung cancer radiotherapy, lung cancer chemotherapy, smoking, exposure to a pollutant, hypersensitivity pneumonitis, a reactive/obstructive lung disease, aspiration chemical pneumonitis/pneumonia, pneumonia, an infection of the nasosinus, intratracheal, intrabronchial or alveolar airspace, a connective tissue disease, Wegener’s granulomatosis, Goodpasture disease, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, medication -rel ted lung injury, cryptogenic organizing pneumonia, Churg- Strauss syndrome, congenital lung disease, or structural lung disease.
  • ARDS acute respiratory distress syndrome
  • HF Heart Failure
  • the controller is coupled to the drug dispenser and thereby administers the initial, adjusted, and titrated dosages of lung active compound.
  • the drug dispenser includes a ventilator coupled to an aerosolizer or a nebulizer.
  • the drug dispenser aerosolizes, nebulizes, or instills the lung active compound.
  • the method further includes, via the controller, receiving a measurement of at least one biomarker the subject measuring pulmonary or cardiac function and determining a pharmacological effect of the dose of lung active compound based at least in part on the at least one biomarker measurement.
  • pulmonary or cardiac function is measured by cardiac output, ejection fraction, stroke volume, or pulmonary capillary occlusion/wedge pressure.
  • the biomarker includes lung water and efficacy of the dose of the lung active compound is determined by the lung water measurement reaching a predetermined value.
  • the biomarker includes lung water and efficacy of the dose of the lung active compound is determined by a change in lung water measurements reaching a predetermined value.
  • the biomarker includes oxygenation index (01), oxygen saturation index (OSI), or PaO2/FiO2, and efficacy of the dose of the lung active compound is determined at least in part based on the 01 measurement, the OSI measurement, or the PaO2/FiO2 reaching a predetermined value.
  • the biomarker includes C-reactive protein (CRP) and efficacy of the dose of the lung active compound is determined at least in part on the CRP measurements reaching a predetermined CRP threshold.
  • CRP C-reactive protein
  • an effective dose of the lung active compound is determined by a plurality of metrics, wherein: a first metric is blood level of the lung active compound, and a secondary metric is lung water measurements, C-reactive protein measurements, 01 measurements, or a combination of two or more secondary metrics.
  • the method further includes reducing oxygen assistance to the subject in response to the efficacy of the lung active compound dose being indicated.
  • this disclosure describes another method of treating a condition in a subject.
  • the method includes administering an initial dose of a lung active compound to the subject’s sinopulmonary via a drug dispenser, then, via a controller after administering the initial dose: receiving a measurement of at least one biomarker from the subject measuring pulmonary or cardiac function, inputting the measurement into a machine learning model that indicates efficacy of the dosage of lung active compound, until the efficacy is indicated from the machine learning model, facilitate providing adjusted dosages of lung active compound to the subject via the drug dispenser, and after the efficacy is indicated from the machine learning model, facilitate administering a titrated dosage of lung active compound to the subject via the drug dispenser.
  • the lung active compound is a thyroid hormone.
  • the thyroid hormone is triiodothyronine (T3 ).
  • the biomarker includes lung water, C-reactive protein, oxygenation, or blood level of the lung active compound.
  • receiving measurement of at least one biomarker includes receiving a combination of measurements that include blood lung active compound measurements, lung water measurements, C-reactive protein measurements, and oxygenation measurements.
  • the condition being treated includes acute respiratory distress syndrome (ARDS), Heart Failure (HF), infant respiratory distress syndrome (IRDS), or myocardial infarction (MI), acute coronary syndrome (ACS), congenital heart disease, structural heart disease, premature birth, chest trauma, pre lung transplant, post lung transplant, ex vivo perfusion, lung cancer radiotherapy, lung cancer chemotherapy, smoking, exposure to a pollutant, hypersensitivity pneumonitis, a reactive/obstructive lung disease, aspiration chemical pneumonitis/pneumonia, pneumonia, an infection of the nasosinus, intratracheal, intrabronchial or alveolar airspace, a connective tissue disease, Wegener’s granulomatosis, Goodpasture disease, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, medication-related lung injury, cryptogenic organizing pneumonia, Churg- Strauss syndrome, congenital lung disease, or structural lung disease.
  • the controller is coupled to the drug dispenser and
  • the drug dispenser includes a ventilator coupled to an aerosolizer or a nebulizer.
  • the drug dispenser instills, aerosolizes, or nebulizes the lung active compound.
  • the method further includes reducing oxygen assistance to the subject in response to the efficacy of the lung active compound dose being indicated.
  • the medical apparatus includes a data interface configured to receive measurements and a processor coupled to the data interface.
  • the processor is configured with instructions operable to receive lung active compound measurements after a baseline dose of lung active compound has been administered to a subject, facilitate providing adjusted dosages of lung active compound to the subject via a drug dispenser until the lung active compound measurements reach an inflection point that indicates efficacy of the dosages of lung active compound, and after the efficacy is indicated, facilitate administering a titrated dosage of lung active compound.
  • the medical apparatus further includes a device interface coupled to the processor, the device interface being coupled to the drug dispenser and thereby administering an initial dose of lung active compound, the adjusted dosages of lung active compound, and the titrated dosages of lung active compound.
  • the drug dispenser includes a ventilator coupled to an aerosolizer or a nebulizer.
  • the drug dispenser instills, aerosolizes, or nebulizes the lung active compound.
  • the processor is further configured with instructions operable to receive a measurement of at least one biomarker from the subject that measures pulmonary or cardiac function and determine the efficacy of the dosages of lung active compound based at least in part on the at least one biomarker measurement.
  • the biomarker includes lung water, C-reactive protein, or oxygenation.
  • the processor receives measurements of a plurality of biomarkers that include a combination of two or more of: blood total lung active compound measurements, free lung active compound measurements, lung water measurements, C- reactive protein measurements, and oxygenation measurements.
  • the processor is further operable to reduce oxygen assistance to the subject in response to the efficacy of the dose of lung active compound being indicated.
  • the medical apparatus includes a data interface configured to receive measurements, a memory storing a machine learning model trained to determine doses of lung active drug administered to a pulmonary tract of a subject, and a processor coupled to the data interface and the memory.
  • the processor is operable to, after a baseline dose of lung active compound has been administered to the subject: receive a measurement of at least one biomarker from the subject measuring pulmonary or cardiac function, inputting the biomarker measurement into a machine learning model that indicates the subsequent dosages of lung active compound, until the efficacy is indicated from the machine learning model, facilitate providing adjusted dosages of lung active compound to the subject via a drug dispenser, and after the efficacy is indicated from the machine learning model, facilitate administering a titrated dosage of lung active compound to the subject via the drug dispenser.
  • the biomarker includes one or more of blood total lung active compound, free lung active compound, lung water, C-reactive protein, or oxygenation.
  • the controller is coupled to the drug dispenser and thereby administers an initial dose of lung active compound, the increased dosages of lung active compound, and the constant dosages of lung active compound.
  • the drug dispenser includes a ventilator coupled to an aerosolizer or a nebulizer.
  • the drug dispenser instills, aerosolizes, or nebulizes the lung active compound.
  • the processor is further operable to reduce oxygen assistance to the subject in response to the efficacy being indicated.
  • FIGS. 1 and 2 are graphs illustrating, as an exemplary embodiment, T3 dosage and biological measurements in response.
  • FIG. 3 is a block diagram of a machine learning model used in a therapy apparatus according to an exemplary embodiment.
  • FIG. 4 is a block diagram of a therapy apparatus control loop according to an exemplary embodiment.
  • FIG. 5 is a flowchart of a therapy algorithm according to an exemplary embodiment.
  • FIG. 6 is a block diagram of a medical apparatus according to an exemplary embodiment.
  • FIG. 7 contains line graphs showing free T3 and total T3 blood levels through four days after the first dose (50 pg, twice daily).
  • A Free T3 concentration (pg/ml).
  • B Total T3 concentration (ng/dL). * Statistically significant difference (p ⁇ 0.05) between treated patients (circles) and control patients (squares).
  • the system may administer a lung active compound — e.g., triiodothyronine (T3), any other thyroid-related hormone, analog, or drug — to treat, for example, pulmonary edema, lung injury, and/or lung inflammation such as, for example, processes that occur in acute respiratory distress syndrome (ARDS).
  • a lung active compound e.g., triiodothyronine (T3), any other thyroid-related hormone, analog, or drug —
  • T3 triiodothyronine
  • any other thyroid-related hormone, analog, or drug e.g., any other thyroid-related hormone, analog, or drug
  • the system may be employed to administer other drugs for machine delivery to treat other indications including, but not limited to, infant respiratory distress syndrome (TRDS), other nasal sinopulmonary diseases, and cardiac illnesses including but not limited to post-myocardial infarction, congestive heart failure (CHF, acute or chronic), cardiac transplant, non-ischemic cardiomyopathies, congenital heart defects.
  • Drug may be delivered directly to the lungs (e.g., by installation, aerosolization, nebulization, etc.) or by continuous infusion of thyroid related hormones, analogs, or drugs.
  • the indication treatable using the system described herein is an acute indication — e.g., where treatment occurs in a hospital, often in the Intensive Care Unit (ICU).
  • the system also may be used to treat chronic conditions where treatment may occur at home or in a non-acute clinical setting.
  • Such chronic conditions include, but are not limited to, heart failure (HF, including but not limited to congestive heart failure, CHF), ex vivo organ perfusion, or any other conditions with chronically reduced cardiac function, pulmonary edema, or pulmonary inflammation.
  • the device managing the automatic and regulated drug delivery can control several types of drug formulations, including but not limited to, a liquid form or an aerosolized form.
  • a liquid formulation may be delivered, for example, by direct instillation via an endotracheal tube.
  • An aerosolized formulation may be delivered, for example, via a nebulizer, an inhaler (e.g., with or without supplemental oxygen, high flow oxygen, etc.), or other method of particulate delivery.
  • Device control feedback mechanisms include measuring at least one selected metric.
  • Suitable metrics include, but are not limited to, at least one biomarker that informs the system of the appropriate dose level, dose frequency, and/or dose duration.
  • suitable biomarkers are biochemical or physiological parameters that include, but are not limited to, parameters found in blood, tissue fluids, exhaled gases, and/or in volatile compounds emitted from the skin.
  • suitable metrics include, but are not limited to, blood T3 level (free T3 and total T3), various lung function metrics to include oxygenation index (01), oxygenation saturation index (OSI), PaO2/FiO2 (P/F ratio), lung fluid levels, and/or inflammation markers such as C- reactive protein.
  • biomarkers of potential use include markers of systemic inflammation and lung injury (including but not limited to IL- 1 , IL-6, IL-8, IL- 10, IL- 18, CXCL-16, serum bicarbonate, TNF-a, sTNF receptor- 1, procalcitonin NEDD9 (neural precursor cell expressed developmentally down-regulated 9), IL-IRA, Fas and Fas ligand, procollagen peptide (PCP) I and III, octane, acetaldehyde, 3 -methylheptane, cytozymes, plasminogen activator inhibitor, protein C, mitochondrial DNA, etc.), lung endothelial injury (e.g., von Willebrand Factor, Angiotensin Converting enzyme activity or quantity, angiopoietin-2, sICAM-1, VEGF, gelsolin, syndecan-1, VCAM, selectins, sTM, etc.), or alveolar epithelial injury (e.g.,
  • the metric values may be reported to device managing the auto administration of drug by the Electronic Health Records (EHR) system or may be manually provided by a human.
  • EHR Electronic Health Records
  • the drug being administered may be formulated to be administered into the lung, whether in a liquid form or as an aerosolized liquid or dry powder.
  • This disclosure further describes methods of treating lung inflammation, lung injury, or pulmonary edema by administering a formulation of drug directly to the nasosinus, endotracheal, intrabronchial, or alveolar space.
  • Acute respiratory distress syndrome causes a marked reduction of T3 in the lung tissue.
  • This deficiency means the lung is less capable of removing fluids when inflamed or in a disease state.
  • both oxygen therapy and mechanical ventilation each of which assists sick patients to be able to breathe and have proper blood O2 levels, can be injurious to lung tissue (e.g., ventilator-associated lung injury, VALI), further compounding the ARDS lung injury.
  • VALI ventilator-associated lung injury
  • Heart Failure also has a severe deficit of T3 in both heart and lung tissue.
  • HF is characterized, at least in part, by inflammation and/or edema in the lungs.
  • Delivering T3 directly to the lung is a preferred administration route since the drug immediately and directly acts on cellular pump mechanisms to remove the excess fluid buildup in the lungs.
  • T3 improves heart function (i.e., contractility).
  • Infant respiratory distress syndrome (IRDS) of prematurity also has a severe deficit of T3. Incomplete gestation shortens the maternal -to-baby development cycle often with incomplete lung development. Human fetal blood levels of T3 and other thyroid hormone rise late in gestation, shortly before birth. Adequate levels of T3, and other hormones, are essential for the lung to begin absorbing the airspace fluid in preparation for the first breath. T3 also is involved in the late gestational production of lung surfactant, another element in lung function for gas exchange and breath. Thus, infants with IRDS often experience pulmonary edema, decreased gas exchange, and resulting hypoxemia.
  • MI myocardial infarction
  • device control feedback mechanisms include measuring at least one selected metric.
  • Suitable metrics include, but are not limited to, at least one biomarker that informs the system of the appropriate dose level, dose frequency, and/or dose duration.
  • suitable biomarkers are biochemical or physiological parameters that include, but are not limited to, parameters found in blood, tissue fluids, exhaled gases, and/or in volatile compounds emitted from the skin.
  • suitable biologic and physiologic metrics include, but are not limited to, blood T3 level (free T3 and total T3), lung water, C-reactive protein (CRP), high-sensitive CRP, O2 levels (e.g., Pat , SpCh, oximetry), CO2 levels (e.g., PaCCh, PvCCh capnography) troponin, lactic acid, oxygenation index (01), oxygenation saturation index (OSI), PaO2/FiO2 (P/F ratio), cardiac output (CO), cardiac index (CI), cardiac contractility, ejection fraction (EF), central venous pressure (CVP), peripheral and central arterial pressure, pulmonary wedge pressure (PWP), systemic vascular resistance (SVR), pre-load/after-load measurements, cerebral perfusion measurements, organ perfusion measurements, VA/VV extracorporeal membrane oxygenation (VA/VV ECMO) settings (e.g., revolutions per minute, RPM; sweep gas flow rate, intra-aortic balloon pump (I
  • a lung condition e.g., ARDS
  • the system and methods described herein can alternatively involve treating alveolar edema and/or inflammation of lung tissue, or lung injury regardless of the underlying cause.
  • Exemplary other causes of lung inflammation or alveolar edema that are treatable using the systems and methods described herein include, for example, myocardial infarction (MI), heart failure (HF), infant respiratory distress syndrome (IRDS), acute coronary syndrome (ACS), congenital heart disease, structural heart disease, premature birth, chest trauma, pre- and/or post-lung transplant, ex vivo perfusion, pre- and/or post- lung cancer radiotherapy or chemotherapy, pneumonia, sepsis, smoking (whether tobacco or THC), exposure to pollutants (whether environmental or occupational, e.g., asbestosis, silicosis, berylliosis, Coal Worker’s, pneumoconiosis, gas exposure, thermal injury, or other pneumoconiosis), hypersensitivity pneumonitis, reactive or obstructive lung diseases (e.g., asthma, chronic bronchitis, reactive airway dysfunction syndrome, or other reactive airway diseases), aspiration chemical pneumonitis or pneumonia, pneumonia or an infection of naso
  • One or more active agents may be formulated with any suitable pharmaceutically acceptable carrier.
  • carrier includes any solvent, dispersion medium, vehicle, coating, diluent, antibacterial, and/or antifungal agent, isotonic agent, absorption delaying agent, buffer, carrier solution, suspension, colloid, and the like. The use of such media and/or agents for pharmaceutical active substances is well known in the art.
  • compositions are incompatible with the active ingredient or is known to be injurious to lung tissue, its use in the therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the active agent or active agents without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • lung active compound includes, but is not limited to, a thyroid-related hormone (e.g., T3), an analog of a thyroid hormone, a thyroid hormone mimetic, a prodrug of a thyroid hormone or of a thyroid hormone-related drug, a deiodinase 3 enzyme, or a deiodinase 3 enzyme inhibitor.
  • the systems and methods can involve administering more than one active agent — i.e., more than one lung active compound — at a time.
  • the system and methods described herein deliver drug — i.e., one or more active agents — directly to tissues of the sinopulmonary tract where therapy is needed.
  • the term “sinopulmonary” refers to tissues of the paranasal sinuses and lungs (i.e., tracheobronchial tree and alveoli).
  • the system and methods described herein may deliver drug to a specific portion of the sinopulmonary tract such as, for example, the pulmonary tract, the trachea, the bronchi, or the alveoli.
  • the term pulmonary tract refers to the lower respiratory system distal to the larynx.
  • T3 reduces the fluid levels in the lung — i.e., reduces pulmonary edema. It also can reduce lung injury and inflammation, thereby decreasing the likelihood of pulmonary fibrosis.
  • the system and methods described herein target delivery of T3 to the lung only, raising T3 only in the lung, differentially, while not affecting systemic T3 for other organs in the body.
  • Acute respiratory distress syndrome is characterized by hemorrhagic inflammatory pulmonary edema with decreased alveolar fluid clearance (AFC) and high mortality.
  • Triiodothyronine acts on alveolar type II pneumocytes to augment their Na,K- ATPase activity, thereby promoting edema fluid clearance and augmenting oxygen diffusion into the capillaries.
  • T3 is inactivated by enzyme iodothyronine deiodinase type-III (D3).
  • D3 enzyme iodothyronine deiodinase type-III
  • D3 expression and activity are elevated in early ARDS human lung tissue.
  • D3 induction in early ARDS is accompanied by local lung T3 inactivation, resulting in a decrease in lung T3 concentration in lung tissue.
  • T3 stimulates alveolar fluid clearance D3-induced inactivation of lung T3 may impede alveolar fluid clearance in ARDS, contributing to the degree of alveolar flooding with fluid and the persistent hypoxemia.
  • deiodinase 3 D3 or DIO3
  • the system could deliver T3 only, D3 inhibitors only, or a combination of T3 and a D3 inhibitor.
  • exemplary deiodinase inhibitors include, but are not limited to, can include iopanoic acid (IOP), iopanoate, ipodate, propylthiourea (PTU), propylthiouracil, 6-propylthiouracil, propranolol, D-propranolol, dexamethasone, cortisol, a glucocorticoid, amiodarone, desethlaminodarone (DEA), dronedarone (Dron), (3'),4',4,6- (tetra)trihydroxyaurone, insulin, 3 ',5 '-cyclic adenosine monophosphate, butyrate, a phenolphthalein dye (e.g., IOP), iopanoate, ipodate
  • Adjustments in oxygen delivery to the patient can be made manually by the clinician and/or the changes may be automated to respond to the measurements of metrics described herein by the system itself, where an algorithm determines the best likely oxygen therapy based on the given metrics for a given therapy.
  • the metrics may include one or more of the following: oxygenation (e.g., Pat , SpO 2 ), ventilator settings (e.g., mean airway pressure, PEEP, tidal volume, FIO2, etc.) lung fluids/water, C-reactive protein, and/or other blood inflammatory markers.
  • the algorithm managing oxygen therapy can use other metrics that may be unique to a given patient or appropriate for the drug being delivered.
  • a selectable combination of manual inputs/outputs together with automated inputs/outputs can be used to provide therapy to patients.
  • treating ARDS by administering T3, T3 can be administered to the lung for the time concurrent improvement of at least one metric — e.g., at least one biological marker or another measurable metric.
  • exemplary metrics include, but are not limited to, lung fluid or water levels, C-reactive protein (CRP) in the blood, and/or systemic or blood T3.
  • Lung water can be measured using a catheter in the femoral artery, with other sensors on the body, connected to hardware/software that calculates the amount of lung water residing in the lung.
  • CRP C-reactive protein
  • Lung water can be measured using a catheter in the femoral artery, with other sensors on the body, connected to hardware/software that calculates the amount of lung water residing in the lung.
  • One such system is the VOLUMEVIEW EVI 000 Clinical Platform (Edwards Lifesciences Corp., Irvine, CA).
  • it can graphically display a picture of a set of human lungs in a light shade of pink, and then overlay from the bottom up, five different rising water fluid levels, low to very high or full.
  • a quick visual picture of the state of the patient s lungs with respect to lung water levels.
  • This is also applicable to other invasive or non-invasive methods, including ultrasound and radiofrequency remote sensing.
  • Metrics such as blood T3 and C-reactive protein (CRP) may be measured using blood tests commonly available at clinics and hospitals.
  • the primary metric is blood T3.
  • the desired dose is realized when the inflection at region 100 occurs. This is then measured as blood T3, which begins to rise, as seen by curve 102.
  • the clinician has reached a steady state dose of T3, so the blood T3 level is more static in its extent.
  • the secondary metric is lung water.
  • the lung epithelial cells augment the transfer of fluid from the lung alveoli into the bloodstream and lymphatic system, in turn resulting in clearing the lungs of fluid and increased kidney excretion of the fluid from the bloodstream, thus clearing the lungs of fluid.
  • This will gradually improve lung function.
  • lung water will begin to fall and will move to a state of minimization.
  • the third metric is C-reactive protein or CRP, which is a general test of the body’s inflammation, offering guidance into the state of the lungs (and injury elsewhere in the body).
  • CRP C-reactive protein
  • Al artificial intelligence
  • This Al algorithm would control the timing, rate, and/or dose of lung active compound to the patient. It could also provide guidance on a preferred application method for a given illness via drug dispenser: instillation (e.g., via fluid dispenser coupled to an endotracheal drip), aerosol or nebulizer (e.g., coupled to a ventilator or other airflow device, or by nasal cannula or another nasal device.
  • instillation e.g., via fluid dispenser coupled to an endotracheal drip
  • aerosol or nebulizer e.g., coupled to a ventilator or other airflow device, or by nasal cannula or another nasal device.
  • the Al algorithm could be implemented in a medical-grade computer control system.
  • FIG. 3 a block diagram illustrates a computer model 300 that may be used in a therapeutic apparatus and system according to an exemplary embodiment for delivery of T3 to a patient.
  • the output 302 of the model 300 is a level of T3 that is applied to the lungs of a patient 304, e.g., via instillation, aerosol, nebulizer, or via nasal cannula or another device.
  • the patient could be on a mechanical ventilator or a heated high flow cannula.
  • Inputs to the model include biological metrics such as measures of blood T3 306, C-reactive protein (CRP) 307, and lung water 308. Other metrics may be used, as indicated by ellipsis 309.
  • Initial conditions 310 may also be input to the model 300 at the beginning of treatment, and may include initial measures of the metrics 306-309, initial dosage of T3, as well as other data of interest related to the patient 304, e.g., sex, weight, initial blood T3 level, etc.
  • the computer model 300 can use an explicit algorithm such as those described in detail below.
  • algorithms can be coded in software and implemented in a medical monitoring/control system.
  • Such software can allow for parameters of operations to be changed in use, e.g., via a user interface operated by the clinician.
  • the software can be implemented in any computer programming language, e.g., C, C++, Java, C#, Python, etc.
  • the computer model 300 may implement at least some of its functionality using an artificial intelligence model such as a machine learning model that may use neural networks and/or artificial intelligence to improve the timeliness and efficacy of drug delivery to individual patients and/or for future patients.
  • an artificial intelligence model such as a machine learning model that may use neural networks and/or artificial intelligence to improve the timeliness and efficacy of drug delivery to individual patients and/or for future patients.
  • a machine learning model implements a framework that can be seen as a “black box” that accepts inputs and produces outputs.
  • the internal structures and/or data of the framework are changed through a training process, in which test data is fed into the model.
  • the model produces outputs from the test data which are compared to known or desired outputs that are also provided as part of the training data.
  • the variances from the actual outputs of the model to the desired outputs of the training data are used to change state variables within the model. The process is repeated until the model achieves a desired state of accuracy or performance in its outputs.
  • a model will be selected that can be used in a time-varying, closed-loop control system as represented in FIG. 3.
  • the T3 drug 302 is the control system input, where the “system” being controlled is the patient 304.
  • the biological measurements 306-309 are feedback variables that are fed into the model 300.
  • the model 300 may be considered a transfer function as defined in classical control theory.
  • a machine learning model suitable for closed-loop control applications may be suitable for use as the model 300 in the illustrated system.
  • ICU patients require 24-hour constant care.
  • Having automated drug delivery, whether in whole or in part, helps reduce clinical care worker tasks and can enhance the likelihood of a faster recovery with fewer side effects from extended ICU treatment.
  • the system described herein learns from the historical record of metrics (e.g., metrics 306 through 309) versus drug dosing and usage and optimizes the drug delivery care routine to maximize health outcomes.
  • the machine learning algorithm may learn that for a given patient’s metrics, a drug should be given once per day, twice per day, three times per day, four times per day, etc. or not at all on a given day.
  • the system may learn that a higher dose in the morning versus the afternoon or evening for a specific patient, with a specific illness, is the optimized therapeutic approach.
  • the system may learn that a higher initial dose is warranted on the first day of treatment. It may also monitor blood level to make sure the level of the drug does not exceed a particular level in the patient’s blood. Periodic blood testing for blood T3 levels can be manually inserted into the drug delivery system or these values can be captured from a medical record database.
  • the systems and methods described herein can involve administering other drugs to the pulmonary tract of a patient to treat other conditions (affecting the lungs, the heart, or other organs) where pulmonary delivery of drug is desired.
  • the exemplary embodiments discussed in detail do not limit the specific metrics selected for monitoring, the number of metrics selected for monitoring, the drug being delivered, the amount of drug being delivered, the frequency at which the drug is delivered, the duration of therapy, or the organ treated by the drug delivered to the lungs.
  • a block diagram shows another example of how the system may control therapy.
  • a T3 dose 400 is applied to the lungs of a patient 404 by way of a ventilator 402, e.g., using a nebulizer or other aerosolization or instillation method.
  • One or more patient metrics 406 are measured repeatedly, such as any combination of the measurements 306-309 shown in FIG. 3.
  • the metrics 406 are input to one or more transfer functions 408 that output one or more system inputs 409 to a controller 410.
  • the controller 410 uses the system inputs 409 to vary one or both of the T3 dose 400 and flow of the ventilator 402.
  • the transfer function 408 can be implemented as any combination of explicit algorithms and artificial intelligence data structures.
  • the system described herein can stand alone as a medical device that is used in conjunction with another medical device (e.g., a ventilator or cardiac device). Alternatively, the system described herein may be a component of a larger cardiac device or pulmonary device.
  • FIG. 5 a flowchart illustrates an example treatment algorithm for patients according to an exemplary embodiment. While illustrated in the context of an exemplary embodiment in which lung water and C reactive protein are secondary metrics that are measured in series, other secondary metrics may be measured and used to determine adjustments to T3 dosing. Determining the proper dosage of T3 for patients with pneumonitis may not include the metric of lung water in certain cases that do not have edema. Thus, other embodiments can involve algorithms that might only use blood T3 values. Still other embodiments may involve algorithms that consider blood T3 values plus CRP values. Metrics may be weighed differently in different embodiments. For example, blood T3 could be weighted more heavily than CRP.
  • lung water levels could become the primary weighted metric with blood T3 levels the secondary metric weighted less heavily.
  • Other algorithms may have a parallel decision tree, but the variables themselves each have a different weight, as just described.
  • a unique combination of serial, parallel, and weighted variable approaches may optimize T3 administration for a given disease and T3 therapeutic delivery approach (e.g., direct instill, aerosol, or nebulizer).
  • the algorithm could be used manually by a clinician and/or in an automated control system.
  • Dosing of T3 is done at step 501 to the lung via direct instill, aerosol or nebulizer delivery of the T3 dose.
  • a baseline level of total and free T3 is measured at 502, resulting from the lung delivered T3 via direct instillation and/or aerosol and/or nebulized methods.
  • decision block 504 and path 506 if the effective dose at 508 is not yet reached, T3 is increased 500.
  • the increase or decrease in dosage can be based on changes in the blood level trough and blood level peak — i.e., to include varying the dosing interval change based on decay kinetics in the lung and transfer from the lung to the blood.
  • T3 can be given as a static dose amount, but the number of initial doses per day could be increased. Although not indicated in the figure, there will be an upper limit in the amount that T3 increases in block 500 to limit harmful side effects.
  • the T3 (blood level) is measured 502 and a determination 504 is made regarding the blood T3 being static or increasing.
  • the primary metric 506 in this example is total and free blood T3 level.
  • the excess T3 is diffused or transported from body areas of higher to lower concentration of T3.
  • this tells the clinician/doctor and/or automated controller a peak dose of T3 has been reached, as determined at block 508.
  • the “peak dose” refers to a dose of T3 that will not have a meaningful additional therapeutic effect. Once the peak dose of T3 has been reached, the therapy thereafter stays at that T3 dose, or some other titrated T3 dose, as indicated at block 510 to maintain that level of T3.
  • titrated dose refers to a dose delivered as ordered by the system via a continuous loop of assessing metrics.
  • a titrated dose may be constant or nearly constant once the peak dose is reached.
  • the titrated dose may vary with time as the system monitors metrics and orders adjustments to the dose to maintain blood levels of the drug within boundaries set for the trough blood level and the peak blood level.
  • FIG. 7A and FIG. 7B show phase 2 clinical trial data for treating patients with Acute Respiratory Distress Syndrome (ARDS) in which blood free T3 and total T3, respectively, are measured after T3 is administered via direct instillation at 50 pg in 10 mL, half to left lung lobe, half to right lung lobe, twice in a 24-hour period.
  • the upper line in each plot is for patients treated with T3 via direct instillation; the lower line is for control patients that did not receive T3.
  • the data indicate that when treating ARDS patients, a higher initial dose than 50 pg of T3 would more quickly restore both lung function and blood levels. After two doses of T3 at 50 pg per dose, blood levels become stable and largely unchanging.
  • the system may increase the initial dose from 50 pg of T3 to 100 pg of T3 to more quickly restore lung function and blood T3 levels.
  • the second dose, 12 hours after the first dose may be 75 pg of T3, and the third dose of 50 pg of T3 may maintain a steady state of lung function and blood T3 levels.
  • the free and total T3 blood (blood) levels are in the lower normal range (as indicated by the greyed box region). Staying in the lower normal range decreases the likelihood and/or extent to which unwanted side effects of cardiac arrhythmias may occur from high or excessive blood free T3 and blood total T3 levels.
  • exemplary secondary metrics 512 lung water and 514 (CRP), which can be used to augment blood T3 data to determining the appropriate T3 dose.
  • One or more secondary metrics can be used by clinicians and/or used in algorithms and/or models if automated and computerized. This process of course can be run manually, where these metrics are used by clinicians to make T3 dosing decisions on a case-by-case, patient- by-patient basis.
  • the primary metric 506 of blood T3 would provide guidance as to the effective T3 dose. Declining or minimized lung water 512 would further support that analysis, as would a lowering of CRP or other biomarkers of lung inflammation, injury, or edema 514. Both of these metrics 512, 514 could also feed into block 508 to indicate that an effective dose has been reached.
  • the process of managing a given indication can use artificial intelligence (dosing machine learning) as more and more data sets are learned from different patient profiles.
  • the data sets for differing illnesses and delivery methods can be used to create training data sets for machine learning models.
  • any other data that is available as part of the data set e.g., hemodynamics, ventilator settings/patient response, blood oxygen levels, PaCh, SpO2, etc.
  • An artificial intelligence approach will offer the clinician a valuable tool to optimize the likely best treatment regimen for a given lung disease or injury.
  • the selected metrics may be evaluated together as a combination, e.g., as a weighted average of normalized values of the metrics, to determine if effective dosage is reached.
  • a subset of the metrics may be used. Exemplary reasons that a measurement may be unavailable include, but are not limited to, a lag in test availability, presence of an underlying condition that makes measurements inconclusive as to lung or heart condition, and the like.
  • multiple artificial intelligence models may be trained and deployed using subsets of the metrics as inputs.
  • T3 can be by instillation, aerosol, nebulizer, and/or indirectly through nasopulmonary delivery.
  • a nebulizer is in its ability to deliver a time-constant dose.
  • an instilled dose is a bolus event, typically every X hours, where X could be every 12 hours or every 24 hours, for example.
  • the instilled dose typically a liquid for instillation into the lung, has a certain half-life and does not maintain a constant delivered drug level to the lung like the nebulizer process. Instillation is mechanically simpler, however, and is often a lower cost option.
  • instillation of a T3 liquid into the lungs may provide higher edema treatment efficacy versus an aerosol form, which cannot easily cross the air-to- lung water transition.
  • the liquid T3 form easily enters the lung water, thereby enhancing the drug’s ability to activate the sodium cellular pump action.
  • An aerosol version could be optimal for extensive spatial lung inflammation, as an aerosol will reach all lung surface areas not impacted by edema.
  • a combination liquid instillation of T3 plus an aerosol, for certain diseases and patients, could therefore be optimal, delivering the advantages of both a liquid and aerosol at the same time.
  • different delivery methods can result in different distributions of the drug within the lungs.
  • both the biological T3 deficiency and T3 improvement mechanisms are the same for humans in as in animal models.
  • the blood level (systemic or blood measurable level) of T3 initially changes more slowly. After the lung has taken up a portion of the applied T3, the blood T3 level will begin to change, causing the lung to off load excess T3 to the body for other organ usage and systemic disposal via the kidneys.
  • T3 steady state concentration
  • different biochemical or physiologic effects may have different maximally effective T3 concentrations.
  • Increasing the level of applied T3 to the lung beyond this value will not improve the outcome, since T3 effects are driven by relative concentrations distributed throughout the body, including other organs, such as the heart.
  • one measure that may be useful in the algorithms and machine learning models is the rate of change of blood T3 over time.
  • a threshold e.g., sufficient change to indicate an inflection point, mathematically the first derivative of the data set
  • Data smoothing e.g., running average
  • the lung will increase removal of edema fluid from the lung. And, on a plot, the level of lung water begins to decrease. As water is removed from the alveolar space, lung function begins to improve, which may be indicated by improved oxygenation, PaCh, and/or SpO2. Oxygenation Index (01) change is an excellent metric to track during lung disease T3 treatment. Furthermore, with improving lung function, the level of oxygen therapy can gradually decrease. Concurrent with lung water, C-reactive protein, a measure of inflammation, will also begin to drop as the effective dose of T3 is reached. Hereto, reducing inflammation improves lung function, and reduces the need for oxygen therapy, albeit on a gradual basis.
  • FIG. 6 a block diagram illustrates details of a medical apparatus 600 according to an exemplary embodiment.
  • the apparatus 600 includes conventional computing hardware, including one or more processors 602, which is shown here as a central processing unit (CPU), although may also include co-processors, digital signal processors, etc.
  • the CPU 602 is coupled to volatile memory 604, which is shown here as random access memory (RAM).
  • RAM random access memory
  • the CPU 602 and RAM 604 are coupled to an input/output bus 606, which may include PCI busses, USB busses, SATA busses, etc.
  • a non-volatile (NV) memory 608 stores data used by the apparatus 600, including operating systems, drivers, user applications, etc.
  • the NV memory 608 may include static RAM, flash memory, disk drives, optical storage, etc. Shown stored in the NV memory 608 is a machine learning model 610 that may be trained and stored as described above.
  • the machine learning model 610 may be run on the CPU 602 and/or specialized hardware, such as a
  • the apparatus 600 includes data input interfaces that include a user interface 614 that receives data 616 from a human operator, e.g., via touchscreen inputs, buttons, switches, keyboards, mice, trackpads, biometric sensors, etc.
  • the user interface 614 may be used for manually inputting data 617 measured elsewhere, such as one or more metrics (e.g., blood T3, CRP, or other metric appropriate for the therapy being delivered to the patient).
  • the data input interfaces may also include device input interfaces 615 such as serial ports, USB ports, network interfaces, etc.
  • the device input interfaces 615 may be used to interface the apparatus 600 with external sensors and/or separate processing devices, such as lung water monitor described above in the context of the exemplary embodiment for delivering T3.
  • network connected blood testing devices may be able to feed test results into the apparatus 600 (or a suitable proxy from which the apparatus 600 can pull the results) as soon as testing is finished.
  • the apparatus 600 or a suitable proxy from which the apparatus 600 can pull the results
  • many hospitals and treatment facilities use patient medical records databases that can deliver data 617 to the apparatus 600.
  • the data collected by the data input interfaces may include any combination of patient biological and physiologic metrics including, but not limited to, blood T3, lung water, C-reactive protein (CRP), high-sensitive CRP, O2, levels (e.g., PaCh, SpCh, oximetry), CO2 levels (e.g., PaCCh, PvCO 2 capnography) troponin, lactic acid, oxygenation index (OI), oxygenation saturation index (OSI), PaO2/FiO2 (P/F ratio), cardiac output (CO), cardiac index (CI), cardiac contractility, ejection fraction (EF), central venous pressure (CVP), peripheral and central arterial pressure, pulmonary wedge pressure (PWP), systemic vascular resistance (SVR), pre-load/after-load measurements, cerebral perfusion measurements, organ perfusion measurements, VA/VV extracorporeal membrane oxygenation (VA/VV ECMO) settings (e.g., revolutions per minute, RPM; sweep gas flow rate , intra-aortic balloon pump (IABP) settings, heart pumps
  • the apparatus 600 includes data output interfaces that include one or more user interfaces 618 that provide outputs 620 to a human operator, e.g., via display, speaker, haptic feedback, indicator lights, etc.
  • the data output interfaces may also include device output interfaces 619 such as serial ports, USB ports, network interfaces, etc.
  • the device output interfaces 615 may be used to interface the apparatus 600 with external devices.
  • the device output interfaces 615 may provide data 621 to a ventilator and/or drug dosing system to control any combination of flow rate (e.g., inspiratory, expiratory, wave morphology, etc ), humidity, volume (e.g., tidal volume), pressure (e.g., positive end- expiratory pressure, PEEP; mean airway pressure, MAP, etc ), oxygen concentration (e.g., fraction inspired oxygen, FIO2), respiration rate, other gases, gas mixture, drug dose, drug concentration, drug dose rate, drug delivery (instillation, aerosol delivery, nebulization, naso- pulmonary delivery, etc.), drug concentration, inspiratory flow rate, etc.
  • flow rate e.g., inspiratory, expiratory, wave morphology, etc
  • humidity e.g., tidal volume
  • pressure e.g., positive end- expiratory pressure, PEEP; mean airway pressure, MAP, etc
  • oxygen concentration e.g., fraction inspired oxygen,
  • the apparatus 600 can be built as a medical-grade device, with appropriate redundancy, power backup, data integrity, and fail-safe algorithms to survive many types of contingent failure modes.
  • the apparatus 600 automate treatment algorithms (e.g., as shown in FIG. 5) in concert with a ventilator for lung delivered drugs or other monitoring device for cardiac indications, and real-time, or near real-time patient data to optimally find the effective dose of drug and maintain that dose during the treatment cycle.
  • the device may be a stand-alone medical-grade device, or integrated into other medical devices, such as a ventilator, heated high flow, mechanical circulatory support devices, ECMO machine for lungs or various heart devices discussed elsewhere in this application.
  • Such therapies can be scaled back automatically via the apparatus 600 as soon as possible, based on biological patient data, thereby reducing the likelihood or extent of harm that such therapies may induce.
  • oxygen therapy is indicated for certain lung indications
  • prolonged pure O2 therapy can irritate lung tissue.
  • the system allows the clinician to scale back O2 therapy as soon as possible, thereby reducing the likelihood and/or extent of lung injury resulting from prolonged O2 therapy.
  • the reduction can be made by changing the percentage of applied oxygen relative to other gases.
  • the reduction in oxygen can also be made by reducing the flow rate and/or total volume of oxygen being delivered. At all points in the process, clinicians could override the automation and go to manual modes.
  • the system-level biological markers provide insight into both the efficacy of lung treatment as well as provide the clinician valuable tools to use during their treatment of patients.
  • the biological markers provide the clinician the tools to both manage each unique patient as well as offer guidance in managing the optimal level of therapy that balances the maximization of patient health and comfort, while minimizing further harm to the patient.
  • the term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Also, the phrases “at least one of,” “comprises at least one of,” and “one or more of’ followed by a list refers to any one of the items in the list and any combination of two or more items in the list.
  • Coupled or “connected” refer to elements being attached to each other either directly (in direct contact with each other) or indirectly (having one or more elements between and attaching the two elements). Either term may be modified by “operatively” and “operably,” which may be used interchangeably, to describe that the coupling or connection is configured to allow the components to interact to carry out at least some functionality.

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Abstract

L'invention concerne un appareil médical qui comprend de manière générale une interface de données configurée pour recevoir des mesures, et un processeur couplé à l'interface de données. Le processeur est configuré avec des instructions servant à recevoir des mesures de principe actif pulmonaire après qu'une dose de référence d'un principe actif pulmonaire a été administrée à un sujet, faciliter la fourniture de dosages ajustés d'un principe actif pulmonaire au sujet par l'intermédiaire d'un distributeur de médicament jusqu'à ce que les mesures de principe actif pulmonaire atteignent un point d'inflexion qui indique l'efficacité des dosages d'un principe actif pulmonaire, et faciliter l'administration d'un dosage constant d'un principe actif pulmonaire après que l'efficacité a été indiquée. Il peut être ordonné à l'appareil de recevoir des mesures de biomarqueurs et d'ajuster des dosages d'un principe actif pulmonaire sur la base, au moins en partie, des mesures de biomarqueurs.
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EP3160565B1 (fr) * 2014-06-30 2021-08-18 Syqe Medical Ltd. Dispositifs et systèmes pour administration pulmonaire d'agents actifs
CN109621228B (zh) * 2018-12-12 2022-06-28 上海联影医疗科技股份有限公司 放射剂量的计算设备、装置和存储介质
US20230147865A1 (en) * 2020-03-27 2023-05-11 Regents Of The University Of Minnesota Compositions and methods for treating pulmonary edema or lung inflammation

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