Providing sequential gas delivery for intermittent hypoxia

Abstract

A system (100) and method (200) for providing intermittent hypoxia using sequential gas delivery to a subject are disclosed. The method (200) includes inducing a normoxic end-tidal partial pressure of oxygen (204) using a sequential gas delivery system within a first specific respiratory rate for a first time period, inducing a hypoxic end-tidal partial pressure of oxygen (208) using the sequential gas delivery system within a second respiratory rate for a second time period, and repeating the steps for a target number of cycles until a therapeutically effective dose of intermittent hypoxia is achieved. The sequential gas delivery system (100) can control the end-tidal partial pressure of carbon dioxide simultaneously and independently of the end-tidal partial pressure of oxygen. The method (200) can be applied in the treatment of a pathological condition in a subject or to improve the subject's health.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 404,505, filed September 7, 2022, entitled "USE OF SEQUENTIAL GAS DELIVERY TO DEVELOP AND ADMINISTER INTERMITTENT HYPOXIA AS THERAPEUTIC MODALITY," the entire contents of which are incorporated herein by reference.

[0002] Field The present disclosure relates to providing intermittent hypoxia. [Background technology]

[0003] Background technology Intermittent hypoxia (IH) offers myriad health benefits. By inducing the expression of hypoxia-inducible factor (HIF), IH triggers a cascade of positive effects throughout the body, including the immune, nervous, cardiovascular, and skeletal systems. It improves physiological function in patients with pulmonary conditions such as chronic obstructive pulmonary disease (COPD), emphysema, and asthma, and preserves breathing in amyotrophic lateral sclerosis (ALS). IH enhances cognitive function in the elderly, reduces depression, and improves quality of life in heart-related diseases. It regulates blood pressure, lipids, and immune responses while combating chronic inflammation. Summary of the Invention [Problem to be solved by the invention]

[0004] Current practice for providing intermittent hypoxia to subjects uses rebreathing circuits or non-rebreathing masks, such as the Everest Summit II™ (Hypoxico Inc., New York, USA), that rely on trial and error to target and maintain hypoxia. Furthermore, the actual arterial concentration of oxygen is unknown and not reproducible. [Means for solving the problem]

[0005] Summary of the Invention One aspect of the present disclosure provides a method for treating a pathological condition in a subject, the method comprising: (a) inducing a normoxic end-tidal concentration of oxygen in the subject within a first respiratory rate using a sequential gas delivery system and maintaining the normoxic end-tidal concentration of oxygen in the subject for a first duration; (b) inducing a hypoxic end-tidal concentration of oxygen in the subject within a second respiratory rate using the sequential gas delivery system and maintaining the hypoxic end-tidal concentration of oxygen in the subject for a second duration; and (c) repeating steps (a) and (b) for a target number of cycles to achieve a therapeutically effective dose.

[0006] The first breathing rate may be 1. The second breathing rate may be 1.

[0007] The pathological condition is one of chronic obstructive pulmonary disease, emphysema, bronchitis, asthma, spinal cord injury, Alzheimer's disease, dementia, depression, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, heart failure, hypertension, metabolic syndrome, inflammatory disease, and pulmonary disease.

[0008] The method may include maintaining an end-tidal concentration of carbon dioxide in the subject using a sequential gas delivery system while performing steps (a)-(c). The method may include: inducing a first end-tidal concentration of carbon dioxide in the subject using the sequential gas delivery system, maintaining the first end-tidal concentration of carbon dioxide while inducing a normoxic end-tidal concentration of oxygen; and inducing a second end-tidal concentration of carbon dioxide in the subject using the sequential gas delivery system, maintaining the second end-tidal concentration of carbon dioxide while inducing a hypoxic end-tidal concentration of oxygen. The first end-tidal concentration of carbon dioxide may be selected to induce a normocapnic state, a hypocapnic state, or a hypercapnic state. The second end-tidal concentration of carbon dioxide may be selected to induce a normocapnic state, a hypocapnic state, or a hypercapnic state.

[0009] The method may include inducing a normoxic end-tidal concentration of oxygen and a normocapnic end-tidal concentration of carbon dioxide during a rest period, and repeating steps (a)-(c) after the rest period. Performing steps (a)-(c) may constitute a set, and the method may include repeating the set for a predetermined number of sets. The method may include repeating the set a predetermined number of times per day and for a predetermined number of days.

[0010] Another aspect of the present disclosure provides a method for improving the health status of a subject, the method comprising: (a) inducing a normoxic end-tidal concentration of oxygen within a first respiratory rate using a sequential gas delivery system and maintaining the normoxic end-tidal concentration of oxygen for a first duration; (b) inducing a hypoxic end-tidal concentration of oxygen within a second respiratory rate using the sequential gas delivery system and maintaining the hypoxic end-tidal concentration of oxygen for a second duration; and (c) repeating steps (a) and (b) for a target number of cycles to achieve a therapeutically effective dose.

[0011] The fitness status is one of exercise tolerance, altitude tolerance, aerobic capacity, and exercise endurance.

[0012] The method may include maintaining an end-tidal concentration of carbon dioxide in the subject using a sequential gas delivery system while performing steps (a) through (c). The method may include: inducing a first end-tidal concentration of carbon dioxide in the subject using the sequential gas delivery system, maintaining the first end-tidal concentration of carbon dioxide while maintaining a normoxic end-tidal concentration of oxygen; and inducing a second end-tidal concentration of carbon dioxide in the subject using the sequential gas delivery system, maintaining the second end-tidal concentration of carbon dioxide while inducing a hypoxic end-tidal concentration of oxygen. The first end-tidal concentration of carbon dioxide may be equivalent to the second end-tidal concentration of carbon dioxide. The first end-tidal concentration of carbon dioxide may be selected to induce a normocapnic state, a hypocapnic state, or a hypercapnic state. The second end-tidal concentration of carbon dioxide may be selected to induce a normocapnic state, a hypocapnic state, or a hypercapnic state. A sequential gas delivery system can be used to maintain an end-tidal concentration of carbon dioxide independent of the subject's breathing rate and pattern, and independent of the end-tidal concentration of oxygen.

[0013] The method may include inducing a normoxic end-tidal concentration of oxygen and a normocapnic end-tidal concentration of carbon dioxide during a rest period, and repeating steps (a)-(c) after the rest period. Performing steps (a)-(c) may constitute a set, and the method may include repeating the set for a predetermined number of sets. The method may include repeating the set a predetermined number of times per day and for a predetermined number of days.

[0014] A further aspect of the present disclosure provides for the use of a sequential gas delivery system in the treatment of a pathological condition.

[0015] A further aspect of the present disclosure provides for the use of a sequential gas delivery system in enhancing wellness.

[0016] A further aspect of the present disclosure provides the use of a sequential gas delivery system to precondition an organ for transplantation.

[0017] A further aspect of the present disclosure provides for the use of a sequential gas delivery system to precondition organs or tissues prior to surgery, during which the blood supply to those organs and tissues may be interrupted.

[0018] A further aspect of the present disclosure provides the use of a sequential gas delivery system to improve bone remodeling.

[0019] A further aspect of the present disclosure provides the use of a sequential gas delivery system to stimulate erythropoietin production in a subject.

[0020] A further aspect of the present disclosure provides a method for determining a therapeutically effective dose of hypoxia. The method also includes: (a) assessing a baseline condition for a subject population; (b) providing intermittent hypoxia to the subject population using a sequential gas delivery system; (d) assessing a post-treatment condition for the subject population; (e) calculating a difference between the baseline condition and the post-treatment condition for the subject population; (f) comparing the calculated differences within the subject population; and (g) determining a therapeutically effective dose of intermittent hypoxia based on the comparison.

[0021] In some embodiments of the method, the subject population may include a test group and a control group, and providing intermittent hypoxia to the subject population may include providing a test dose of intermittent hypoxia to the test group; and providing a control dose of intermittent hypoxia to the control group. The test dose and control dose of intermittent hypoxia may be characterized by at least one of the partial pressure of end-tidal oxygen induced during normoxia, the partial pressure of end-tidal oxygen induced during hypoxia, the partial pressure of carbon dioxide induced during normoxia, the partial pressure of carbon dioxide induced during hypoxia, a first period, a second period, a target number of cycles, a rest period, a total number of sets, a target number of sets per day, and a target number of days. Comparing the calculated difference within the subject population may include comparing the calculated difference for the test group with the calculated difference for the control group. The subject population is selected to share a common attribute. The common attribute may be one of a health condition, a pathological condition, gender, age, race, weight, and height. The common attributes are one of chronic obstructive pulmonary disease, emphysema, bronchitis, asthma, spinal cord injury, Alzheimer's disease, dementia, depression, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, heart failure, hypertension, metabolic syndrome, inflammatory disease, and pulmonary disease.

[0022] These, together with other aspects and advantages which will become apparent hereinafter, reside in the details of construction and operation as more fully described and claimed hereinafter, reference being made to the accompanying drawings which form a part hereof, and in which like numerals refer to like parts throughout.

[0023] The embodiments will be described with reference to the following drawings. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a block diagram of a system for providing intermittent hypoxia. [Figure 2] 1 is a flow chart of a method for providing intermittent hypoxia. [Figure 3] 3 is a graph illustrating an exemplary performance of one embodiment of the method of FIG. 2. [Figure 4] 3 is a flowchart illustrating an exemplary implementation of another embodiment of the method of FIG. 2. [Figure 5] 5 is a graph illustrating an exemplary performance of one embodiment of the method of FIG. 4. [Figure 6] 3 is a flowchart illustrating an exemplary implementation of another embodiment of the method of FIG. 2. [Figure 7] 1 is a flow chart of a method for determining a therapeutically effective dose of hypoxia. DETAILED DESCRIPTION OF THE INVENTION

[0025] MODE FOR CARRYING OUT THE INVENTION List of abbreviations The following abbreviations are used herein: [Table 1]

[0026] definition As used herein, "about" refers to a range of ±20% of the numerical value that follows. In one example, the term "about" refers to a range of ±10% of the numerical value that follows. In one example, the term "about" refers to a range of ±5% of the numerical value that follows.

[0027] "Dose" herein refers to the amount and frequency of hypoxia provided to a subject during treatment for intermittent hypoxia. The dose includes the P induced during hypoxia. et O2, duration of hypoxia, P induced during normoxia et O2, duration of normoxia, first P ET CO2, the second P ET These include, but are not limited to, CO2, number of cycles, rest periods, total sets, sets per day, number of days, or a combination thereof.

[0028] As used herein, "health condition" refers to the anatomical, physiological, or mental state of a subject.

[0029] "Hypercapnic" as used herein refers to blood with abnormally high CO2 levels. Generally, hypercapnic P a CO2 exceeds approximately 45mmHg.

[0030] "Hyperoxic" herein refers to blood with abnormally high O2 levels. Generally, hyperoxic P a O2 exceeds approximately 100 mmHg.

[0031] "Hypocapnic" as used herein refers to blood with abnormally low CO2 levels. Generally, hypocapnic P a CO2 is less than about 35 mmHg.

[0032] "Hypoxic" herein refers to blood with abnormally low O2 levels. Generally, hypoxic P a O2 is less than about 80 mmHg.

[0033] "Neucapnic" as used herein refers to blood with normal CO2 levels. Generally, normocapnic P a CO2 is about 30mmHg to about 50mmHg.

[0034] "Normoxic" herein refers to blood with normal O2 levels. Generally, normoxic P a O2 ranges from about 70mmHg to about 110mmHg.

[0035] As used herein, a "pathological condition" refers to an abnormal anatomical, physiological, or psychological manifestation of a disease in a subject.

[0036] As used herein, a "therapeutically effective dose" refers to the minimum dose of intermittent hypoxia that provides a therapeutic benefit to a subject.

[0037] Systems and methods The present disclosure provides improved systems and methods for providing intermittent hypoxia to a subject.

[0038] FIG. 1 is a block diagram of a system for providing intermittent hypoxia to a subject.

[0039] The system 100 includes a sequential gas delivery (SGD) system for providing sequential gas delivery to a subject 130. The system 100 measures the end-tidal partial pressure of oxygen (P ET The system 100 includes a gas source 103, a gas blender 104, a mask 108, a processor 110, and a memory 112. In some embodiments, the system 100 includes a user interface 114. The system 100 controls P by generating a gas flow prediction to activate a target end-tidal value. ET End-tidal partial pressure of O2 and carbon dioxide (P ET The system 100 is configured to control the amount of CO2 ET O2 can be targeted independently of the subject's breathing rate and pattern. ET O2 is the target P ET It can be targeted independently of CO2.

[0040] In a particular embodiment, system 100 is RespirAct™ (Thornhill Medical™, Toronto, Canada). For more information regarding sequential gas delivery, reference may be made to U.S. Pat. No. 8,844,528, U.S. Patent Application Publication No. 2018 / 0043117, and U.S. Pat. No. 10,850,052, which are incorporated herein by reference.

[0041] The gas source 103 may supply, for example, carbon dioxide (CO), oxygen (O), nitrogen (N), and air at controllable rates as defined by the processor 110. Non-limiting examples of gas mixtures that may be supplied to the gas source 103 are as follows: Gas A: 10% O2, 90% N2; Gas B: 10% O2, 90% CO2; Gas C: 100% O2; and Calibration gas: 10% O2, 9% CO2, 81% N2.

[0042] The gas blender 104 is connected to the gas supply 103, receives gases from the gas supply 103, and blends the received gases as controlled by the processor 110 to obtain a gas mixture such as a first gas (G1) and a second gas (G2) for sequential gas delivery.

[0043] The second gas (G2) is a neutral gas in the sense that it has a partial pressure of carbon dioxide (PCO2) approximately equal to that of the gas exhaled by the subject 130, which contains about 4% to 5% carbon dioxide. In some examples, the second gas (G2) may include the gas actually exhaled by the subject 130. The first gas (G1) is a neutral gas having a target PCO2. ET It has an oxygen partial pressure (PO2) equal to O2 and preferably does not have a significant amount of carbon dioxide. For example, the first gas (G1) may be air (typically having about 0.04% carbon dioxide), or it may be composed of 21% oxygen and 79% nitrogen, or it may be a gas of similar composition, preferably with little or no CO2.

[0044] The processor 110 may control the gas blender 104, such as by electronic valves, to deliver the gas mixture in a controlled manner.

[0045] The mask 108 is connected to the gas blender 104 and delivers gas to the subject 130. The mask 108 may be sealed to the subject's face to ensure that the subject inhales only the gas supplied to the mask 108 by the gas blender 104. In some examples, the mask is sealed to the subject's face with skin tape, such as Tegaderm™ (3M, St. Paul, Minnesota). A valve device 106 may be provided in the system 100 to limit the subject's inhalation to the gas supplied by the gas blender 104 and limit exhalation to the room. In the example shown, the valve device 106 includes an inhalation one-way valve from the gas blender 104 to the mask 108, a branch between the inhalation one-way valve and the mask 108, and an exhalation one-way valve at the branch. Thus, the subject 130 inhales gas from the gas blender 104 and exhales gas to the room.

[0046] The gas source 103, gas blender 104, and mask 108 may be physically connectable by conduits 109, such as piping, for carrying gas. One or more sensors 132 may be located in the gas blender 104, mask 108, and / or conduit 109 to sense gas flow rate, pressure, temperature, and / or similar properties and provide this information to the processor 110. Gas properties may be sensed at any suitable location to measure the properties of gases inhaled and / or exhaled by the subject 130.

[0047] The processor 110 may include a central processing unit (CPU), microcontroller, microprocessor, processing core, field programmable gate array (FPGA), application specific integrated circuit (ASIC), or similar device capable of executing instructions. The processor 110 may be connected to and cooperate with memory 112 that stores instructions and data. As used herein, the term "processor" may refer to a single processor or multiple processors, either co-located or at different locations, that cooperate to perform the described functions.

[0048] Memory 112 includes a non-transitory machine-readable medium, such as an electronic, magnetic, optical, or other physical storage device that encodes instructions. The medium may include, for example, random access memory (RAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), flash memory, storage drives, optical devices, etc.

[0049] The user interface 114 may include a display device, a speaker, a microphone, a touch screen, a mouse, a keyboard, buttons, etc., or a combination thereof, to allow for operator input and / or output.

[0050] Instructions 120 may be provided to perform the functions and methods described herein. Instructions 120 may be directly executable, such as a binary file, and / or may include interpretable code, bytecode, source code, or similar instructions that may be subjected to further processing to be performed. Instructions 120 may be stored in memory 112.

[0051] 2 is a flow chart illustrating an exemplary method for providing intermittent hypoxia to a subject. Method 200 may be implemented by instructions 120 controlling system 100.

[0052] In block 204, the processor 110 controls the system 100 to measure the normoxic end-tidal partial pressure of oxygen (P ET O2).

[0053] Using the system 100, normoxic P ET In a specific example, normoxic P ET O2 is introduced into the first respiratory rate. In a specific example, hypoxic P ET O2 is induced within one breath. In a further example, hypoxic P ET O2 is induced within 2 breaths. In yet a further example, hypoxic PET O2 is induced within 3 breaths. ET If O2 is hypoxic, normoxic P ET O2 can be achieved within one breath, or advantageously within one second.

[0054] The system 100 may be configured to generate normoxic P for a first duration. ET Maintain O2. In a specific, non-limiting example, the first duration is about 5 minutes. In a specific, non-limiting example, the first duration is about 4 minutes. In another non-limiting example, the first duration is about 3 minutes. In another non-limiting example, the first duration is about 2 minutes. In another non-limiting example, the first duration is about 1 minute.

[0055] Normoxic P ET O2 may be selected to induce a blood oxygen saturation that is considered normal for the human body. In certain instances, normoxic P ET O2 is from about 70 mmHg to about 110 mmHg. ET O2 is from about 95 mmHg to about 100 mmHg. In a specific example, normoxic P ET O2 is approximately 95mmHg.

[0056] At block 208, the processor 110 detects hypoxic P in the subject 130. ET The system 100 is controlled to induce O2. Using the system 100, hypoxia can be achieved quickly. In some instances, hypoxic P ET O2 can be induced within 1 minute, or preferably within 30 seconds. ET O2 can be induced within the second respiratory rate. In a specific example, hypoxic P ET O2 is induced within one breath. In a further example, hypoxic P ET O2 is induced within 2 breaths. In yet a further example, hypoxic P ET O2 is induced within 3 breaths.

[0057] The system 100 controls the hypoxic P for a second duration. ET Maintain O2. In a specific, non-limiting example, the second duration is about 180 seconds. In a further non-limiting example, the second duration is about 120 seconds. In a specific, non-limiting example, the second duration is about 90 seconds. In another non-limiting example, the second duration is about 60 seconds. In another non-limiting example, the second duration is about 40 seconds. In another non-limiting example, the second duration is about 20 seconds.

[0058] Hypoxic P ET O2 may be selected to induce blood oxygen saturation that is considered to be low for the human body. In certain instances, hypoxic P ET O2 is from about 40 mmHg to about 80 mmHg. In a specific, non-limiting example, normoxic P ET O2 is approximately 40 mmHg. In another non-limiting example, normoxic P ET O2 is approximately 50 mmHg. In a specific, non-limiting example, normoxic P ET O2 is approximately 60 mmHg. In a specific, non-limiting example, normoxic P ET O2 is approximately 70 mmHg. In a specific, non-limiting example, normoxic P ET O2 is approximately 80 mmHg. Generally, P less than 40 mmHg ET O2 is considered harmful and should be avoided.

[0059] As will be appreciated by those skilled in the art, blocks 204 and 208 may be performed in any order. In some examples, the system 100 may be configured to: ET Induce O2 and then normoxic P ET In another example, the system 100 induces normoxic P ET Induce O2 and then hypoxic P ETIn a further example, the system 100 may generate a baseline P ET Aim for O2.

[0060] The system 100 can target normoxic and hypoxic end-tidal concentrations of oxygen in a subject, regardless of the subject's breathing rate and pattern.

[0061] As part of blocks 204 and 208, the system 100 ET The end-tidal partial pressure of carbon dioxide (P ET In some examples, the system 100 may control the P ET Subjects were given normocapnic P ET In another example, the system 100 ET Hypercapnic P with varying O2 ET In a further example, the system 100 ET Hypocapnic P with varying O2 ET In a further example, the system 100 induces normoxic P during execution of block 204. ET Induce CO2 and hypercapnic P while performing block 208 ET In a further example, the system 100 may induce hypocapnic P during execution of block 204. ET Induce CO2 and normocapnic P while performing block 208 ET In a further example, the system 100 may induce hypercapnic P during execution of block 204. ET Induce CO2 and normocapnic P while performing block 208 ET Inducing CO2. Inducing hypercapnia during method 200 enhances the therapeutic effects of intermittent hypoxia.

[0062] Generally, normocapnic P ET CO2 is a partial pressure of CO2 of about 30 mmHg to 50 mmHg. Generally, hypercapnic PET CO2 is a CO2 partial pressure greater than 45 mmHg. Generally, hypocapnic P ET CO2 is considered to be a CO2 partial pressure of less than 35 mmHg.

[0063] In block 212, the processor 110 determines whether the target number of cycles has been reached. Each repetition of blocks 204 through 208 is referred to herein as a cycle. Generally, the target number of cycles is selected to achieve a therapeutically effective dose of intermittent hypoxia.

[0064] In a specific, non-limiting example, the target number of cycles is 2. In a specific, non-limiting example, the target number of cycles is 4. In a specific, non-limiting example, the target number of cycles is 6. In a specific, non-limiting example, the target number of cycles is 8. In a specific, non-limiting example, the target number of cycles is 10. In a specific, non-limiting example, the target number of cycles is 12. In a specific, non-limiting example, the target number of cycles is 14. In a specific, non-limiting example, the target number of cycles is 18. In a specific, non-limiting example, the target number of cycles is 20.

[0065] Upon execution of block 212, the target number of cycles may be retrieved from memory 112 or may be received as an input at user interface 114. In some examples, the target number of cycles is selected according to subject demographics, subject identity, disease, treatment goals, target number of sets per day, target number of days, or a combination thereof.

[0066] If the processor 110 determines that the target number of cycles has not been reached, the method 200 returns to block 204 and repeats blocks 204 and 208 for another cycle.

[0067] If the processor 110 determines that the target number of cycles has been reached, the method 200 ends. As part of block 212, the processor 110 may control the user interface 114 to output a message indicating that the mask 108 can be removed. In some examples, if the processor 110 determines that the target number of cycles has been reached, the processor 110 may ET It will be appreciated that after execution of method 200, normoxic P ET Targeting O2 may allow the subject 130 to breathe comfortably until the mask 108 is removed.

[0068] 3 is a graph illustrating an exemplary implementation of method 200. Time is on the x-axis and P ET O2. N indicates that the system 100 is in normoxic P ET represents the first duration of inducing O2, and H represents the time period during which the system 100 induces hypoxic P ET represents the second duration for inducing O2, and C represents cycles. In this example, blocks 204 and 208 are executed three times, so the number of cycles C is 3, but the number of cycles C is not particularly limited.

[0069] 3, the first duration N is approximately equal to the second duration H, but the first and second durations are not particularly limited. In other examples, the first duration N is longer than the second duration H. In yet other examples, the second duration H is longer than the first duration N.

[0070] FIG. 4 illustrates another exemplary implementation of method 200 in which blocks 204 through 212 are repeated.

[0071] After processor 110 determines in block 212 that the target number of cycles has been reached, the method proceeds to block 404. In block 404, processor 110 determines whether the target number of sets has been reached. Each repetition of blocks 204 through 212 is referred to herein as a set. Generally, the target number of sets is selected to achieve a therapeutically effective dose.

[0072] In a specific, non-limiting example, the target number of sets is 1. In a specific, non-limiting example, the target number of sets is 2. In a specific, non-limiting example, the target number of sets is 4. In a specific, non-limiting example, the target number of sets is 6. In a specific, non-limiting example, the target number of sets is 8.

[0073] Upon execution of block 212, the target number of sets may be retrieved from memory 112 or may be received as an input at user interface 114. In some examples, the target number of sets is selected according to subject demographics, subject identity, disease, treatment goal, number of previous sets, target number of sets per day, target number of days, target number of subsequent sets, or a combination thereof.

[0074] If the processor 110 determines that the target number of sets has not been reached, the method 200 proceeds to block 408. At block 408, the processor 110 outputs a pause signal during the pause period.

[0075] In a specific, non-limiting example, the rest period is about 5 minutes. In a specific, non-limiting example, the rest period is about 4 minutes. In another non-limiting example, the rest period is about 3 minutes. In another non-limiting example, the rest period is about 2 minutes. In another non-limiting example, the rest period is about 1 minute. In another non-limiting example, the rest period is about 30 seconds.

[0076] In response to receiving the pause signal, the user interface 114 may output a message indicating that a set is complete. The message may further communicate to the user that another set is needed. The message may further communicate to the user the duration of the pause period, where the pause period corresponds to the duration between the end of the previous set and the beginning of the next set. The message may include, but is not limited to, text, an image, a pre-recorded audio message, a light, or a combination thereof. In a specific, non-limiting example, the pause signal controls the user interface 114 to display a countdown timer displaying the time remaining until the pause period ends. In a further non-limiting example, the user interface 114 includes a speaker that plays a pre-recorded audio message indicating when the pause period has ended.

[0077] Once the pause period has ended, method 200 returns to block 204. In some examples, method 200 returns to block 204 only after processor 110 receives a resume signal input at user interface 114. During the pause period, subject 130 may have removed mask 108. The resume signal confirms to processor 110 that subject 130 is ready to begin another set.

[0078] If the processor 110 determines that the target number of sets has been reached, the method 200 ends. As part of block 404, the processor 110 may control the user interface 114 to output a message indicating that treatment is complete. The message may include, but is not limited to, text, an image, a pre-recorded audio message, a light, or a combination thereof. In a particular example, the processor 110 controls the user interface 114 to display a message indicating that the mask 108 can be removed from the subject 130.

[0079] In some examples, if the processor 110 determines that the target number of sets has been reached, the processor 110 mayET It will be appreciated that after execution of method 200, normoxic P ET Targeting O2 may allow the subject 130 to breathe comfortably until the mask 108 is removed from the subject 130.

[0080] 5 is a graph illustrating an exemplary implementation of method 200 in which blocks 204 through 212 are repeated. Time is on the x-axis and P is on the y-axis. ET 1, the mask 108 is removed from the subject 130 during the rest period R, and the system 100 does not deliver gas to the subject 130 during the rest period R. In this example, the system 100 induces normoxia during the rest period R, but the system 100 is not particularly limited thereto. In another example, the system 100 induces hyperoxia during the rest period R. In yet another example, the subject 130 removes the mask 108 during the rest period R, and the system 100 does not deliver gas to the subject 130 during the rest period R.

[0081] Method 200 may be repeated over the course of a treatment plan. In some non-limiting examples, method 200 is repeated two or more times per day. In non-limiting examples, method 200 is repeated daily, weekly, biweekly, monthly, or bimonthly. Method 200 may be repeated until a desired physiological outcome is achieved.

[0082] Prior to inducing intermittent hypoxia in a subject, a treatment may be selected, as shown in Figure 6. Block 604 involves selecting a treatment plan and is performed before block 204 in method 200. The treatment plan includes parameters for providing a dose of intermittent hypoxia to the subject. The parameters include: a first period, a normoxic P ET O2, second period, hypoxic P ET O 2、 The first P ET CO2, the second P ET These include, but are not limited to, CO2, target number of cycles, target number of sets, rest period R, target number of sets per day, target number of days, or combinations thereof.

[0083] In some examples, block 604 includes receiving input at user interface 114, the input including treatment plan parameters. In response to receiving the parameters, processor 110 controls system 100 to perform method 200 according to the parameters entered at user interface 114.

[0084] In other examples, block 604 includes retrieving a treatment plan from memory 112. In these examples, memory 112 stores a database including one or more treatment plans. The one or more treatment plans include parameters for delivering a dose of intermittent hypoxia. The parameters are stored in memory 112 in association with one or more reference attributes. The reference attributes include, but are not limited to, the subject's identity, age, sex, race, weight, height, lung capacity, health status, reason for treatment, and combinations thereof. As part of block 604, user interface 114 receives input indicating one or more attributes of subject 130. In response to receiving the input, processor 110 retrieves a treatment plan from memory 112, and the retrieved treatment plan is selected based on a comparison of the subject attributes with the reference attributes stored in the database. Method 200 is then performed according to the parameters of the retrieved treatment plan to provide the subject 130 with a dose of intermittent hypoxia.

[0085] The system 100 and method 200 have many practical applications.

[0086] System 100 can be used to treat pulmonary disorders, including, but not limited to, chronic obstructive pulmonary disease, emphysema, bronchitis, and asthma. System 100 can be used to apply intermittent hypoxia to improve ventilatory and cardiovascular function in patients with pulmonary disorders.

[0087] The system 100 can be used to treat spinal cord injuries. The system 100 can be used to apply intermittent hypoxia to improve motor and respiratory function after spinal cord injury.

[0088] The system 100 can be used to improve cognitive function in elderly individuals. The system 100 can be used to improve cognitive function in subjects with Alzheimer's disease or dementia.

[0089] The system 100 can be used to treat depression.

[0090] System 100 can be used to treat cardiovascular disorders, including, but not limited to, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, and heart failure. System 100 can be used to apply intermittent hypoxia to improve physical performance and quality of life in subjects with cardiovascular disorders.

[0091] The system 100 can be used to treat hypertension.

[0092] The system 100 can be used to treat metabolic syndrome. The system 100 can be used to normalize abnormal lipid metabolism.

[0093] The system 100 can be used to treat chronic systemic inflammation.

[0094] The system 100 can be used to pre-condition tissue or organs for surgery.

[0095] The system 100 can be used to precondition tissue or organs for surgery, particularly surgery that is likely to interrupt the blood supply to the tissue or organ. In some examples, the surgery is organ or tissue transplantation. During transplantation, the organ or tissue is deprived of oxygen for the period it takes to remove the organ or tissue from the donor and reattach the organ or tissue to the recipient's blood vessels. As a result, the organ or tissue may experience oxidative stress, ischemia, and reperfusion syndrome. While cooling the organ or tissue can extend its lifespan, ice crystals cause cellular damage. The system 100 described herein can be used to improve transplant outcomes. By performing the method 200 on the donor prior to transplantation, the organ or tissue develops tolerance to hypoxia, which can extend the lifespan of the organ or tissue and improve outcomes for the recipient.

[0096] System 100 can be used to increase the aerobic capacity of a subject. In a specific, non-limiting example, system 100 is used to increase the aerobic capacity of an elderly male. In a specific, non-limiting example, system 100 is used to increase the aerobic capacity of an athlete.

[0097] The system 100 can be used to stimulate erythropoietin production in a subject.

[0098] System 100 can be used to control metabolic syndrome. In particular, system 100 can be used to reduce weight, lower cholesterol, normalize blood sugar levels, and increase insulin sensitivity.

[0099] The system 100 can be used to improve bone remodeling. The system 100 can be used to increase osteoblast formation. The system 100 can be used to inhibit osteoclast formation.

[0100] 7 is a flow chart illustrating a method 700 for determining a therapeutically effective dose of intermittent hypoxia. In FIG. 7, the method 700 is performed by the system 100.

[0101] At block 704, system 100 receives baseline conditions for the subject population. As part of block 704, system 100 may receive the baseline conditions as input received at user interface 114. The baseline conditions may include, but are not limited to, cardiovascular function, respiratory function, cognitive function, memory, reflexes, coordination, strength, mood, cerebrospinal fluid (CSF) composition, blood composition, weight, exercise tolerance, altitude tolerance, aerobic capacity, exercise endurance, or combinations thereof. Generally, system 100 receives the baseline conditions for each subject in the subject population.

[0102] At block 706, the system 100 provides intermittent hypoxia to the subject population. The intermittent hypoxia may be provided according to method 200.

[0103] In some examples, the subject population includes at least one test group and at least one control group. The test group is administered a test dose of intermittent hypoxia, and the control group is administered a control dose of intermittent hypoxia that is different from the test dose. The test dose and control dose of intermittent hypoxia include, but are not limited to, the partial pressure of end-tidal oxygen induced during normoxia, the partial pressure of end-tidal oxygen induced during hypoxia, the partial pressure of carbon dioxide induced during normoxia, the partial pressure of carbon dioxide induced during hypoxia, the first period, the second period, the target number of cycles, the rest period, the total number of sets, the target number of sets per day, the target number of days, and combinations thereof. In some examples, the control group is not administered intermittent hypoxia.

[0104] It should be understood by one skilled in the art that the subject population may include multiple test groups and multiple control groups to assess the effectiveness of multiple doses of intermittent hypoxia.

[0105] In some examples, the test and control groups are selected to share a common attribute. Common attributes include, but are not limited to, a health condition, a pathological condition, gender, age, race, weight, height, or a combination thereof. In examples where the common attribute is a pathological condition, common attributes include, but are not limited to, chronic obstructive pulmonary disease, emphysema, bronchitis, asthma, spinal cord injury, Alzheimer's disease, dementia, depression, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, heart failure, hypertension, metabolic syndrome, inflammatory disease, pulmonary disease, or a combination thereof. In examples where the common attribute is a health condition, common attributes include, but are not limited to, exercise tolerance, altitude tolerance, aerobic capacity, and exercise endurance.

[0106] At block 708, the system 100 receives a post-treatment status for the subject population. As part of block 708, the system 100 may receive the post-treatment status as input received at the user interface 114. The post-treatment status may include, but is not limited to, cardiovascular function, respiratory function, cognitive function, memory, reflexes, coordination, strength, mood, cerebrospinal fluid (CSF) composition, blood composition, weight, exercise tolerance, altitude tolerance, aerobic capacity, exercise endurance, or a combination thereof. For comparison, the post-treatment status typically corresponds to a baseline status. Generally, the system 100 receives a post-treatment status for each subject in the subject population.

[0107] In block 710, the processor 110 calculates the difference between the baseline state and the post-treatment state for the subject population. The difference between the baseline state and the post-treatment state can indicate the effectiveness of intermittent hypoxia for each individual. In some instances, the difference between the baseline state and the post-treatment state is a positive value, indicating that the subject's condition improved after receiving a dose of intermittent hypoxia. In other instances, the difference between the baseline state and the post-treatment state is a negative value, indicating that the subject's condition deteriorated after receiving treatment. In further instances, the difference between the baseline state and the post-treatment state is zero or negligible, indicating that the dose had no effect on the subject.

[0108] In block 712, processor 110 compares the calculated differences within the populations. In examples where the populations include a test group and a control group, block 712 includes comparing the calculated difference for the test group to the calculated difference for the control group. The comparison may include any suitable statistical method known in the art.

[0109] In block 714, processor 110 determines a therapeutically effective dose of intermittent hypoxia based on the comparison in block 712. If the condition of the subjects in the test group is improved compared to the condition of the subjects in the control group, the test dose of intermittent hypoxia is therapeutically effective.

[0110] While method 700 has been described with respect to a subject population, it should be understood that a variation of method 700 may alternatively be used to determine a therapeutically effective dose for an individual. In this variation, the individual's condition is assessed before and after a first dose of intermittent hypoxia and before and after a second dose of intermittent hypoxia. Processor 110 compares the change in condition resulting from the first dose with the change in condition resulting from the second dose to determine whether the first or second dose of intermittent hypoxia is therapeutically effective.

[0111] It will now be apparent to those skilled in the art that the present disclosure provides certain advantages over the prior art. The current practice of providing intermittent hypoxia to a subject is to use a non-respiratory mask to deliver controlled concentrations of oxygen to the subject. These devices are ET It relies on incremental trial and error to target and maintain O2, which extends cycle time and source gas consumption. a Targeting O2 may change with slight ventilation and act as a confounding factor. a It prevents the coordinated regulation of CO2. a O2 is unknown and reproducibility cannot be guaranteed.

[0112] In contrast, system 100 and method 200 use sequential gas delivery to ET The system 100 targets O2 quickly and accurately, improving the subject's tolerance to treatment, reducing source gas usage, and ensuring that the subject receives a therapeutic dose without reaching damaging levels of hypoxia. ET P regardless of O2 ET CO2 can be controlled, which enhances the effects of intermittent hypoxia. Importantly, method 200 is reproducible, ensuring consistency between treatments and, for the first time, allowing providers to determine the efficacy of hypoxia dosing. Method 200 and system 100 can be used to confirm therapeutic doses for individuals or populations.

[0113] The many features and advantages of the present invention are apparent from the detailed specification, and it is, therefore, intended by the appended claims to cover all such features and advantages of the present invention that fall within the true spirit and scope of the invention. Further, because numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and therefore, reference may be made to all suitable modifications and equivalents that are within the scope of the invention.

Claims

1. A sequential gas delivery system for use in providing intermittent hypoxia to a target, The aforementioned sequential gas delivery system is Gas supply source, A gas blender for receiving gas from the aforementioned gas supply source and blending the received gas, A processor for controlling the gas blender to blend the received gas to obtain a gas mixture, A mask connected to the gas blender and configured to deliver the gas mixture to the target, A memory for storing instructions that can be executed by the processor to control the sequential gas delivery system, Includes, The aforementioned sequential gas delivery system is (a) Induce a normal end-tidal concentration of oxygen in the subject within a first respiratory rate, and maintain the normal end-tidal concentration of oxygen in the subject for a first duration. (b) Induce a hypoxic end-tidal concentration of oxygen in the subject within a second respiratory rate, and maintain the hypoxic end-tidal concentration of oxygen in the subject for a second duration. (c) Repeat (a) and (b) for the target number of cycles to achieve an effective therapeutic dose. A sequential gas delivery system characterized by being configured as follows.

2. The sequential gas delivery system according to claim 1, wherein the first respiratory rate is 1 and the second respiratory rate is 1.

3. The sequential gas delivery system according to claim 1, wherein the normal oxygen and hypoxic end-tidal concentrations of oxygen in the subject are controlled independently of the degree and pattern of breathing of the subject.

4. The sequential gas delivery system is (a) to (c) while maintaining the end-exhaled concentration of carbon dioxide in the subject. The sequential gas delivery system according to claim 1, further configured as follows.

5. The sequential gas delivery system is In the subject, a first end-tidal concentration of carbon dioxide is induced, and the first end-tidal concentration of carbon dioxide is maintained while inducing the normal end-tidal concentration of oxygen. In the subject, a second end-tidal concentration of carbon dioxide is induced, and the second end-tidal concentration of carbon dioxide is maintained while inducing the hypoxic end-tidal concentration of oxygen. The sequential gas delivery system according to claim 1, further configured as follows.

6. The sequential gas delivery system according to claim 5, wherein the first end-tidal concentration of carbon dioxide is selected to induce a normal carbon dioxide state, and the second end-tidal concentration of carbon dioxide is selected to induce a hypercarbon dioxide state.

7. The sequential gas delivery system is During the rest period, the normal oxygen end-tidal concentration and the normal carbon dioxide end-tidal concentration are induced in the subject. After the aforementioned pause period, repeat (a) through (c). The sequential gas delivery system according to claim 1, further configured as follows.

8. (a) The execution of (c) constitutes a set, The aforementioned sequential gas delivery system is The set is repeated for a predetermined number of sets. The sequential gas delivery system according to claim 7, further configured as follows.

9. The sequential gas delivery system is The above set is repeated a predetermined number of times per day. The sequential gas delivery system according to claim 8, further configured as follows.

10. The sequential gas delivery system is Repeat the above set for a predetermined number of days. The sequential gas delivery system according to claim 9, further configured as follows.

11. The sequential gas delivery system according to any one of claims 1 to 10, wherein the pathological condition is one of chronic obstructive pulmonary disease, emphysema, bronchitis, asthma, spinal cord injury, Alzheimer's disease, dementia, depression, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, heart failure, hypertension, metabolic syndrome, inflammatory disease, and lung disease.

12. A sequential gas delivery system for use in the treatment of pathological conditions, preferably the sequential gas delivery system according to claim 1, The aforementioned pathological conditions include one of the following: chronic obstructive pulmonary disease, emphysema, bronchitis, asthma, spinal cord injury, Alzheimer's disease, dementia, depression, myocardial ischemia, angina pectoris, myocardial infarction, coronary artery disease, heart failure, hypertension, metabolic syndrome, inflammatory diseases, and lung diseases. A sequential gas delivery system, preferably the sequential gas delivery system described in claim 1.

13. A sequential gas delivery system for use in enhancing health, preferably the sequential gas delivery system according to claim 1, The aforementioned health condition is one of the following: exercise tolerance, high tolerance, aerobic capacity, and exercise endurance. A sequential gas delivery system, preferably the sequential gas delivery system described in claim 1.

14. A sequential gas delivery system for use in pre-conditioning an organ or tissue before surgery, including organ or tissue transplantation, preferably the sequential gas delivery system according to claim 1.

15. A sequential gas delivery system for use to improve bone remodeling or to stimulate erythropoietin production in a subject, preferably the sequential gas delivery system according to claim 1.

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