Enhanced expiratory rebreathing device

Abstract

Preferred embodiments relate to devices and methods for stabilizing breathing during sleep including providing a face mask having a trap, the mask assembly defining a reservoir to retain CO2 from exhaled breath by a user; retaining CO2 from the exhaled breath, wherein the reservoir comprises a plurality of cavities that each retain a portion of exhaled CO2; and recirculating at least a portion of the retained CO2 to the user in one or more subsequent breathing cycles.

Description

[0001] Docket No.: 122295-07320

[0002] Enhanced Expiratory Rebreathing Device Background

[0003] This application claims priority to U.S. provisional patent application no. 63 / 691,806 filed on September 6, 2024, and also to U.S. provisional patent application no. 63 / 700,472 filed on September 27, 2024, the entire contents of the above applications being incorporated herein by reference.

[0004] Patients with sleep disordered breathing (SDB) have variable contributions from upper airway obstruction and abnormal control of breathing. The latter is best demonstrated by Cheyne-Stokes respiration (e.g., in congestive cardiac failure), but a lesser degree of periodic breathing is a common finding in clinical practice. Even those who have obstructive sleep apnea (OSA) as conventionally defined have the majority of respiratory events determined by drive fluctuations (neural drive-dependent respiratory events). The greater the contribution from abnormal or unstable control, the less effective are therapies based on air pressure support of the upper airway, such as continuous or bilevel positive airway pressure (CPAP or BiPAP). Additional oxygen is a commonly used therapeutic adjunct, even if hypoxia is not severe, but does not fully treat periodic breathing.

[0005] It has been known for over fifty years that disordered carbon dioxide homeostasis in the blood is fundamental to the development of periodic breathing patterns. It has also been known that increasing the concentration of CO2 in inspired air by 2-6% has a profound and immediate stabilizing effect on respiration during sleep. Supplemental CO2 stabilizes breathing by damping the variations in CO2 concentration in the blood caused by hyperventilation and hypoventilation, and by increasing the average partial pressure of CO2 in the blood.

[0006] Control of breathing during sleep is critically dependent on the level of carbon dioxide (CO2), especially in non-rapid eye movement (NREM) sleep. There is a level of CO2

[0007] 1

[0008] MEl\57694243.vl Docket No.: 122295-07320 that enables stable breathing, and a level where there is the start of instability, which is called the NREM CO2 apneic threshold. Once this threshold is crossed, a central apnea or hypopnea occurs. When CO2 level rises, breathing is restored.

[0009] There are several types of central sleep apnea (CSA), where breathing drive stops and starts. CO2 may be too high from inadequate breathing, called hypercapnic CSA, which may be seen in conditions such as high spinal cord injury, chronic lung disease, and obesity. CO2 may be too low due to overventilation, called hypocapnic CSA, commonly seen in heart failure, after stroke, at high altitude, and in about 30% of those who have what seems like obstructive sleep apnea. There is a third form where the rhythm of breathing is irregular, and may be called ataxic CSA, and seen with use of drugs like opioids and baclofen, and after injury to the brainstem. In all these conditions, the level of CO2 is important as lowering this level below the apnea threshold will worsen CSA.

[0010] Traditional positive airway pressure uses a vented mask and enough pressure to prevent rebreathing (pressures in the range of 3-5 cms results in CO2 rebreathing), while typical clinically applied pressures (8-15 cms H2O) results in CO2 washout. This is appropriate for obstructive sleep apnea with a high CO2 reserve, but where there is a drop in CO2 this is not likely to induce respiratory instability.

[0011] In those who have hypocapnic CSA, the breathing control system is too sensitive to changes in oxygen and CO2, thus resulting in cycles of overventilation and underventilation. Thus, the current standard configuration enhances respiratory instability in those so predisposed. Non-intuitively, a controlled increase of rebreathing is a strategy to improve respiratory stability. As the CO2 fluctuates, breathing also fluctuates in NREM sleep. This pattern generally does not occur in REM sleep, but rarely can be experienced by patients at extreme high altitude or with severe heart failure. Keeping the CO2 steady (reducing its

[0012] 2

[0013] MEl\57694243.vl Docket No.: 122295-07320 fluctuations) makes breathing more stable, even if CO2 is kept just above the apnea threshold. That is, there is no need to raise the CO2 to stabilize breathing, but reduce its fluctuations.

[0014] Summary

[0015] The following relates to devices and methods for fabricating and using face mask assemblies and devices to improve sleeping patterns of patients experiencing sleep apnea or hypopnea. Preferred configurations for the face mask assembly include a face mask with a trapping space or volume in which expired CO2 is retained in the trap volume so that during a subsequent inhalation period the user will inhale the expired CO2 and consequently reduce or eliminate further disruption of sleep. The amount of the trap space can be adjusted depending on the degree to which the user requires an additional volume of trapped exhaled CO2 to be effective in avoiding sleep disruption. This provides for stabilization that can be done by slightly increasing CO2 in the air and by rebreathing CO2. There is a significant advantage to combining positive pressure with CO2 rebreathing as the positive pressure stabilizes the airway and the rebreathing stabilizes the CO2. With this combination of features in a single treatment the net effect is greater than the sum of parts.

[0016] The mask assemblies described herein can be coupled to a modulated continuous positive airway pressure system. The air flow output of a CPAP system can be ambient room air coupled to the mask assembly or can be mixed with a regulated amount of CO2 and the regulated flow is delivered to the mask assembly. The regulated CO2 system can be operated by a mobile computing device such as a mobile phone, tablet computer or laptop computer, or can be configured in a single housing as a portable standalone unit that can be connected to a CO2 source. With the use of regulated CO2 or a mixture thereof with oxygen (carbogen) can provide an unexpected level of stabilization in breathing for many patients by rebreathing CO2. The regulated air pressure system can be configured in separate modules as described

[0017] 3

[0018] MEl\57694243.vl Docket No.: 122295-07320 herein, or in a single unit having a housing including electromechanical components and a display, that weighs less than 20 pounds (about 9 kg) less than 10 pounds (about 4.54 kg) or preferably less than 5 pounds (about 2.27 kg), that is hand portable, and can operate with battery power during one or more treatment sessions extending for at least four to six hours or more depending on the condition of the patient. The regulated air pressure device can optionally be connected to an external supply of carbon dioxide and / or oxygen to provide a level of continuous positive pressure during sleep. A low level of CO2 can be used at less than 5% CO2 depending upon the condition of the patient. A level in a range of 1-2 % can preferably be used although levels that are greater than zero and less than 4% can be effective to sustain a level or rebreathing of CO2 depending on how well the mask assembly provides a seal that substantially prevents leakage during the treatment session.

[0019] In preferred examples of operation, the amount of CO2 change that is needed to stabilize breathing in hypocapnic CSA can be determined by using a combination of medical conditions and patterns of CSA. The CSA which occurs in the presence of heart failure, atrial fibrillation or stroke is almost always more hypocapnia than in the absence of such conditions, and thus, needs more CO2 stabilization. The cycle length of the CSA also helps, as when short (for example, 30 seconds or less), and heart function is usually good so that the severity of CO2 reductions is smaller (less time for CO2 to drop and rise), while with longer cycle CSA, the severity of fluctuations of CO2 is larger (more time for CO2 drops and rises). Thus, more trap space, or additional enhanced respiratory rebreathing space (EERS) is usually needed when the cycle length is longer. Finally, the loop gain (control sensitivity) of the breathing system can be calculated from breathing signals, and the higher the loop gain, the more EERS is needed. Thus, using these three factors, a prediction (personalization) of the EERS needed can be made for each patient. A preferred implementation can include at least three distinct levels of the trap volume, which for example, can be 50-75 cc (no medical

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[0021] MEl\57694243.vl Docket No.: 122295-07320 condition, short [e.g. 30 seconds or less] cycle, mild-moderate elevation of loop gain), 75 to 100 cc (medical condition, intermediate [e.g. 31-60 seconds] cycles, moderate-severe elevation loop gain), and 100-150 cc (medical condition, long [e.g. over 60 seconds] cycle. As each method of loop gain estimation uses a slightly different calibration, the exact thresholds are determined by which method is used. As the pattern of breathing including cycle length can be tracked by various respiratory measurement approaches, adjustments to the trap volume can be readily made to improve effectiveness. Automated methods for computing loop gain can be used as described herein that serve to establish when traditional CPAP treatment will fail and indicate which patients will benefit from the systems and methods described herein.

[0022] The plurality of different trap volumes can be implemented using different embodiments such as the use of a plurality of different mask attachments that a user can assemble for use. In one embodiment, the mask can include one or more chambers or channels to provide a first volume of trap space, such as 50-75 cc, in a first mask chamber as described herein. The mask can also include a second volume of trap space, such as an additional 25 cc, in a second mask chamber that can be fluidly coupled to the flow path in the mask by opening and closing a valve, for example. A third volume of the trap space can comprise a tube that can be attached to the mask by a user. Additional volumes can optionally be included in the mask during fabrication or attached to the mask. The mask preferably does not include any vents that would cause CO2 to leak during use. Thus, the mask has a contact surface that forms a fluid impermeable contact seal with the skin of the user to reduce gas exchange around the edge of the mask. Thus, preferred mask assemblies include a ventless face mask with a selectable number of trap volumes wherein the total trap volume is selected based on a screening process of the patient.

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[0024] MEl\57694243.vl Docket No.: 122295-07320

[0025] A further embodiment employs an outer tube attached to the mask that surrounds a plurality of smaller diameter tubes positioned within the outer tube. Flow in the EERS tube is turbulent, given mixing of exhalation and incoming positive airway pressure. The multi-tube configuration provides a more laminar flow and reduces mixing, enabling better trapping of CO2. The plurality of smaller tubes can be configured to provide the desired trap volume appropriate for the patient, or alternatively can define a second and / or third trap volumes as required for the user. One or more of the plurality of smaller diameter tubes can be flexible so that they expand with the increase in pressure that results in exhalation during the breathing cycle. The elastic properties of the flexible tubes serve to increase the volume of retained CO2 without substantially increasing the flow resistance.

[0026] The systems and methods described herein can be used to assess the condition of the patient to determine whether traditional methods such as CPAP will fail in treating the patient. When the condition is properly classified for treatment, the mask assemblies and positive pressure breathing devices provide more effective treatment for sleeping disorders. The systems and methods described herein can utilize computational methods for automatically classifying the condition of the patient based upon measured breathing cycle data.

[0027] Brief Description of the Drawings

[0028] Fig. l is a schematic diagram of the modulated air pressure system for an embodiment of the present invention.

[0029] Fig. 2A is a schematic diagram of the mask assembly having a variable trap space connected to a modulated air pressure device.

[0030] Fig. 2B is a detailed view of the modulated air pressure device of Fig. 2A.

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[0032] MEl\57694243.vl Docket No.: 122295-07320

[0033] Fig. 3 is a schematic diagram of a method of stabilizing breathing during sleep according to an embodiment of the present invention.

[0034] Fig. 4 illustrates turbulent airflow arising from the mixing of exhalation flow and incoming positive airway pressure that can dilute expired CO2.

[0035] Fig. 5 schematically illustrates a multilumen tube with exhaust ports for a plurality of tube lumens transporting exhalation from the patient in which a safety flap for an antiasphyxiation valve.

[0036] Fig. 6 is a schematic diagram of a multilumen tube portion of a variable trap space mask assembly in one embodiment of the present invention.

[0037] Fig. 7 depicts enlargement of the interior volume or expansion of at least a portion of the interior tube elements of the multilumen tube of Fig. 5

[0038] Fig. 8 is a perspective view of multilumen tube of a mask for linearized airflow in which a portion of the interior tube lumens convey the incoming CO2 mixed with atmospheric air across the length of the multilumen tube to reduce mixing with the expired CO2.

[0039] Fig. 9 is a top view of a converted non-vented mask forming a fluid impermeable seal with the skin of the patient according to an embodiment of the present invention.

[0040] FIG. 10 depicts a swivel valve attached the mask of Fig. 9.

[0041] FIG. 11 is a front perspective view of the mounted ventless mask.

[0042] FIG. 12 shows polysomnography of a patient including baseline PSG, standard CPAP titration, and CPAP with rebreathing of CO2 as described herein.

[0043] FIGs, 13A-13C illustrate an automated method for analysis of breathing patterns for the classification of patients for treatment.

[0044] FIG. 14 is a process flow diagram illustrating a method for classification and treatment of patients.

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[0046] MEl\57694243.vl Docket No.: 122295-07320

[0047] Detailed Description of the Drawings

[0048] Reference will now be made in detail to various embodiments of the disclosed devices and methods, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

[0049] In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Any range described herein will be understood to include the endpoints and all values between the endpoints.

[0050] The use of a trap space with positive airway pressure is called enhanced expiratory rebreathing space, or EERS. The primary function of EERS is to reduce the amount of CO2 blown off when the patient arouses at the end of apnea or hypopnea (when breathing resumes or overshoots). There is no need to “raise” the CO2, which is a problem with large amounts of dead space or high levels of inhaled CO2.

[0051] By identifying patients who can be suitable for EERS therapy prior to CPAP failure, there is the potential for improved long-term compliance and acceptance of CPAP therapy. 80% of patients treated with EERS had given up therapy; the long-term salvage rate at longterm follow-up was about 50%. Embodiments of EERS therapy have been employed on over 1,000 patients with over 10,000 patient years of use. Prior attempts to utilize rebreathing in the treatment of sleep apnea are described in Gilmartin et al., Treatment of Positive Airway Pressure Treatment-Associated Respiratory Instability with Enhanced Expiratory Rebreathing Space (EERS), Journal of Clinical Sleep Medicine, Vol. 6, No. 6 (2010) and also in U.S. Patent No. 7,886,740, the entire contents of which is incorporated herein by reference.

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[0053] MEl\57694243.vl Docket No.: 122295-07320

[0054] The present rebreathing devices and methods can utilize the mask assemblies described herein with a Positive Airway Pressure Gas Modulator (PAPGAM) system. As shown in Fig. 1, the system 10 includes a mask 60 worn by the patient that is connected by a tube to the PAPGAM or modulator system 24. The modulator system 24 is an instrument designed to deliver precisely metered concentrations of medical -grade CO2, in conjunction with conventional continuous positive airway pressure (CPAP) therapy 12. Modulator system 24 contains a proportional valve 26 (Pneutronics, Hollis, New Hampshire) under computer control 40 with controller 22 which modulates the delivery of the CO2 gas into a chamber 27 where it is mixed with pressurized room air from a positive airway pressure machine 12. The positive airway pressure unit 12 can include an air input 18, an air filter 19, a control panel 21 that operates a flow actuator such as a fan or blower that drives the air though the tube 14 into the chamber 27 of unit 24. The positive airway pressure unit 12 can optionally include a heater 15 and / or a tank 17 for water to humidify the air delivered to the modulator unit 24. The CO2 can be provided in steel cylinders or other sources 50, such as canisters containing five pounds of liquid CO2, for example. A pressure regulator 52 mounted on the tank 17 delivers gas to the PAPGAM 24 at pressures such as at 10 pounds per square inch (PSI) of gas. Air in the mixing chamber 27 is continuously sampled for CO2 concentration with sensor 29, and the data are input into the computer 40 or a memory 29 in the regulator housing 24. Gas from an oxygen concentrator can also be injected into the mixing chamber 27 via fixtures built into the PAPGAM 24. The mixed gases are then delivered via a hose to a specially prepared sealed oronasal mask, which optionally incorporates a CO2 sensor (Nihon Kohden, Tokyo, Japan). Mirage (ResMed, Sydney, Australia) and Spectrum (Respironics, Murrysville, Pennsylvania, USA) full face masks that have been treated with a plastic sealant at potential points of leak are used to provide a ventless mask, further supported by metallized tape, and the CO2 sensor is placed immediately between the tubing and the mask. The mask-mounted

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[0056] MEl\57694243.vl Docket No.: 122295-07320 sensor thus provides an accurate waveform of inspired and expired CO2 as long as the mask remains substantially sealed. Data from the mask sensor are input into the computer and can optionally be used to control the proportional valve while data from the mixing chamber 27 are used as a back-up safety monitor. A data-acquisition card installed in the computer provides data inputs and control outputs to the CPAP 12 and regulator unit 24. DASYLab 7.0 (National Instruments, Austin, Texas, USA) running under the Windows XP Professional operating system (Microsoft Corporation, Redmond, Washington, USA) controls the PAPGAM 24. The instrument is remotely operable via wireless ethemet connection 25 to a laptop computer, tablet or an internet enabled mobile phone or other portable communication device 40. The user is presented with a screen at the laptop or mobile computing device, which includes an interface such as a keyboard and / or touchscreen configured to adjust the dosage set point, readouts of operating and physiologic values, and alarm indicators. Once a dosage has been selected, the PAPGAM 24 automatically maintains that dosage within a very narrow range using a proportional / integral / derivative closed-loop control program. All operating parameters of the PAPGAM 24 as well as the CO2 waveform and blood-gas data from CO2 monitor or sensors are recorded and stored on the computer hard drive. Means of synchronizing these data with the usual polysomnographic recording are provided. For many patients, there is an immediate (< 1 minute) response to the addition of 0.5% to 1% carbon dioxide, and minimal changes were required during sleep.

[0057] Note that natural dead space alone has been used to treat central sleep apnea, but required 300-500 cc rebreathing. This results in a 3% or higher increase in inhaled CO2, the added work of increasing tidal volumes to compensate for increased dead space, and the associated discomfort. Residual apnea is also common - that is, partial effectiveness. The present system uses sub-tidal volume trap space in the mask volume, and due to the synergism between positive pressure and CO2 stabilization, there is no hypercapnia.

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[0059] MEl\57694243.vl Docket No.: 122295-07320

[0060] EERS may be accomplished by covering traditional exhalation ports on positive airway pressure masks and adding small additional tubing with distal exhalation and safety valves. This technique reduces CO2 blow-off during arousals and the associated large recovery breaths, typically producing a maximal increase in resting CO2 by 1-2 mmHg, thus increasing the CO2 reserve and making it less likely to encounter the hypocapnic apneic threshold.

[0061] The amount of CO2 change that is needed to stabilize breathing in hypocapnic CSA can be determined by using a combination of medical conditions and patterns of CSA. The CSA which occurs in the presence of heart failure, atrial failure or stroke is almost always more hypocapnia than in the absence of such conditions, and thus, needs more CO2 stabilization. The cycle length of the CSA also helps, as when short (30 seconds or less), heart function is usually good and the severity of CO2 reductions is smaller (less time for CO2 to drop and rise), while with longer cycle CSA the severity of fluctuations of CO2 is larger (more time for CO2 drops and rises). Thus, more EERS is usually needed when the cycle length is longer. Finally, the loop gain (control sensitivity) of the breathing system can be calculated from breathing signals, and the higher the loop gain, the more EERS is needed. Thus, using these three factors, a prediction (personalization) of the EERS needed can be made. A simple rule could be 50-75 (no medical condition, short [30 seconds or less] cycle, mild-moderate elevation of loop gain), 75 to 100 (medical condition, intermediate [31-60 seconds] cycles, moderate-severe elevation loop gain), and 100-150 cc (medical condition, long [over 60 seconds] cycle. As each method of loop gain estimation uses a slightly different calibration, the exact thresholds are determined by which method is used. As the pattern of breathing including cycle length can be tracked by various respiratory measurement approaches, adjustments can be readily made.

[0062] 11

[0063] MEl\57694243.vl Docket No.: 122295-07320

[0064] In those with CSA, high loop gain and hypocapnia can be a key destabilizer of sleeprespiration. The hypercapnic ventilatory response is in fact elevated in idiopathic CSA.

[0065] The sleep-related arousal threshold describes the ease with which an individual can be triggered to arouse from sleep, with a low arousal threshold suggesting that even mild stressors (respiratory or non -respiratory) can lead to an arousal. Conversely, a high arousal threshold suggests that a high amplitude stressor is required to disrupt sleep. In the context of sleep apnea, a low threshold will lead to more frequent sleep wake transitions and has adverse consequences for tolerance of positive pressure therapy. These frequent arousals result is excessive CO2 blow-off, which can be prevented by EERS. Thus EERS is useful for those who have a low arousal threshold by reducing or eliminating post-arousal instability of respiration.

[0066] Polysomnographic features suggestive of high loop gain and low arousal threshold are depicted in Table 1 :

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[0068] MEl\57694243.vl Docket No.: 122295-07320

[0069] Loop gain refers to the relation of a response to a disturbance, for sleep apnea the ratio of ventilatory response in reaction to a ventilatory stimulus. When the loop gain is higher than desirable, there is a disproportionately robust ventilatory response, and when lower than desirable, an over-damped system. A vigorous ventilatory response may seem advantageous compared to the alternative, a low loop gain leading to an insufficient ventilatory response, and hence a tendency to hypoventilation. However, high loop gain causes its own challenges given the control mechanisms governing respiration in sleep. Loop gain can be further classified as controller gain, mixing gain, and plant gain. Controller gain refers to the sensitivity of the system to changes in chemical stimuli like carbon dioxide and is governed by central and peripheral chemoreceptors. High controller gain suggests that a given change in PaCCL will result in a greater change in ventilation, while a low controller gain will generate a lesser response in ventilation for the same change in PaCCL. In sleep apnea, intermittent nocturnal hypoxia sensitizes the carotid body and results in a steeper slope of the hypoxic ventilatory response and elevated controller gain. Plant gain refers to the efficiency of gas exchange within the respiratory system; it is dependent on the characteristics of the individual’s cardiopulmonary systems. An individual without cardiopulmonary comorbidities will have a higher percentage of their lung volume participating in efficient gas exchange. A normal pulmonary system leads to more change in gas levels per change in minute ventilation than an individual with, for example, advanced chronic obstructive lung disease (COPD). The COPD patient has lower plant gain and is less

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[0071] MEl\57694243.vl Docket No.: 122295-07320 likely to produce a large change in CO2 for a given change in ventilation. In a system with high loop gain, a low efficiency of gas exchange can actually help prevent hypocapnia and hence the resultant overshooting of the ventilatory response. In addition, an “arousal gain” can be considered a modifier, with more vigorous arousals a result of greater effective controller gain. Mixing gain is most relevant in conditions like heart failure with a prolonged circulation time.

[0072] The relative contribution of pathologic features in different sleep apnea endotypes is depicted in Table 2:

[0073] The control of ventilation is quite different in the states of wake and sleep. Inputs are much more numerous during wakefulness and include the peripheral and central chemoreceptor response to multiple molecules including oxygen, hydrogen ions, CO2, nitric oxide, and hydrogen sulfide; input from temperature and pain stimuli; lung stretch; emotional stimuli; and voluntary control of breathing. The influence of most of these inputs wanes with a transition to sleep. In the sleep state, voluntary and emotional stimuli are absent and respiration during non-rapid eye movement (NREM) sleep is largely governed by chemical drivers. Specifically, CO2 becomes the key respiratory driver, such that hypercapnic respiratory response is the greatest determinant of ventilatory drive during sleep. The NREM CO2 threshold is just a few mmHg lower than CO2 values under eupnea. The CO2 reserve,

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[0075] MEl\57694243.vl Docket No.: 122295-07320 therefore, is the space where CO2 may fluctuate without triggering ventilatory instability, CO2 reserve is low in those with hypocapnic CSA, periodic breathing, or TE-CSA.

[0076] Patients with high loop gain, such as those with congestive heart failure and idiopathic CSA, lack the typical degree of hypoventilation with transition to sleep and the ventilatory response to CO2 below eupneic values is more sensitive. This combination makes it more likely for these high loop gain CHF patients to reach the hypocapnic induced apneic threshold.

[0077] EERS has a few possible effects to enable respiratory stability. First, by using EERS, loop gain is lowered through reduction in plant gain, by reducing CO2 removal with ventilation. Second, by slightly raising baseline CO2 (1-2 mmHg), the likelihood of hitting the NREM CO2 threshold is reduced, and the CO2 reserve is therefore increased. Third, the greatest effect of EERS may be during intermittent arousal-induced ventilatory blow-off (a “shock-absorber” effect), preventing the major resulting fluctuations of CO2 that inevitably occur. Finally, there may be effects at the level of cerebral blood flow. Generally, there is no change in mean heart rate or respiratory rate.

[0078] In certain exemplary embodiments of systems and methods for treating patients with high loop gain, it is advantageous to classify those patients for which the treatments described herein are best suited. This can aid in the selection of the volume of rebreathing that is best suited for a particular patient. Automated methods of assessment and classification of patients have been developed in which computational methods can be used to score patients whereby the specific therapy required can be more predictably applied. One such method is described in Oppersma et al., Algorithm for automatic detection of self-similarity and prediction of residual central respiratory events during continuous positive airway pressure; Sleep Research Society (Sleep J), 2021, 1-9, the entire contents thereof being incorporated herein by reference. The Oppersma et al. publication describes an automated process for labeling

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[0080] MEl\57694243.vl Docket No.: 122295-07320 central apneas and hypopneas wherein a software product available from Matlab (R2019A), Natick MA, USA, the envelope of an abdominal and / or chest RIP (respiratory inductance plethysmography) band tracing was calculated automatically in which the envelope function computes the upper and lower envelopes of the recorded signal. Increases in the difference between the upper and lower envelopes using a discrete Fourier transform yielded data for the detection breathing events sufficient to detect the occurrence of sleep apnea with the calculation of a central apnea index (CAI). Logistic regression with 5-fold cross-validation can be applied to predict residual central events during CPAP. After further studies of this method, further improvements were made to improve the recognition of high loop gain as a diagnostic indicator of conditions where controlling CO2 level can assist in treatment. See Nassi et al., Morphological Prediction of CPAP Associated Acute Respiratory Instability; American Journal of Respiratory and Critical Care Medicine; 10.1513 / AnnalsATS.202311- 979OC (2024). Further details concerning the described methods can be found in US application No. 63 / 558,429 filed on February 27, 2024 and entitled Method of Detecting and Tracking Respiratory Control Instability and Expressed High Loop Gain by Self-Similarity Analysis by Nassi et al, the entire contents of this application being incorporated herein by reference.

[0081] An embodiment of the present Positive Airway Pressure Gas Modulator (PAPGAM) is a device configured for patient use to deliver precisely metered doses of carbon dioxide gas (CO2), oxygen (O2), and potentially other inhalational agents to patients who are also being treated with positive airway pressure (PAP). The PAPGAM is designed to meet the need for such an instrument in treatment of unstable breathing, including sleep apnea, periodic breathing and central apnea. These conditions affect millions of people worldwide and result in substantial morbidity and mortality.

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[0083] MEl\57694243.vl Docket No.: 122295-07320

[0084] Precise metering of CO2 is important as there is the potential for adverse side effects if an overdose is given. Metering must be maintained over a range of demand conditions. In addition, there can be clinical utility to varying the dosage over time as a function of the physiological response of the patient. As a result, closed loop control based on physiological data obtained from the patient in real time is an important feature of an embodiment of the PAPGAM system.

[0085] An exemplary embodiment can employ a non-vented sleep apnea mask or a vented mask may be adapted by sealing the vents for use in the disclosed invention. Fig. 2 depicts a non-vented mask according to an embodiment of the present invention. EERS may be achieved by blocking the mask exhaust vents to prevent normal CO2 escape. One option is to convert a vented mask which adds 70 (when converting nasal masks) to 100 (when converting oronasal masks) cc’s of trap space to the disclosed system.

[0086] Alternatively, and in the embodiments described below, additional EERS volumes may then be added by inserted corrugated flexible tubing in 50 cc increments to the mask tubing, with the ability to add 50-150 cc’s total of EERS to the system. A swivel valve, for example Whisper Swivel II Exhalation Valve by Phillips, which allows for continuous venting and thus represents the termination of the non-vented breathing circuit, may be added at the distal end of the EES tubing to allow for exhalation of CO2.

[0087] In full-face mask setups, a safety valve 204 or flap (i.e., non-rebreathing valve, Fig. 4) is added to prevent theoretical asphyxiation in the event of power outage or machine malfunction, but can be optional in nasal only masks. Exhaust ports 206 associated with different lumens of the multilumen tube 200 are configured to provide a trapping volume 202 in tube 200 for EERS as described herein.

[0088] One of the features of the disclosed system is CO2 biocalibration. With a non-vented mask, a CO2 sensor, and no positive airway pressure, resting wake end-tidal CO2 is measured,

[0089] 17

[0090] MEl\57694243.vl Docket No.: 122295-07320 followed by the change in CO2 with the addition of 50, 100, and 150 cc of trap space. The sensor may be placed at the mask outlet, and may be able to capture the exhaled stream and provide a clear ETCO2 “plateau” in most instances. This measurement is quite sensitive to leak around the edges of the ventless mask, and thus a very good fit providing a fluid tight seal is necessary for accurate tracking during sleep.

[0091] The measurement may be started with a non-vented mask with CPAP pressures at the lowest reasonable pressure to address obstruction (e.g., 6-8 cmEEO). The decision to start the measurement with additional EERS (50-150 cc’s) may be individualized and dependent on 1) a perceived level of underlying loop gain abnormality, 2) starting CO2 levels obtained prior to measurement, and 3) the patient’s tendency for prolonged sleep latency and poor sleep consolidation.

[0092] As the measurement progresses, pressures may be increased for clear flow-limitation and obstructive events, which typically predominate in REM sleep. Periodic (particularly short-cycle) obstructive events, especially in NREM sleep, should raise suspicion for high loop gain as a primary driver of the respiratory instability and aggressive up-titration of pressures should be avoided in favor of the addition of EERS if possible. It is often useful to intermittently and frequently review respiratory patterns in a five to ten minute window; this can help to visualize more subtle waxing and waning respiratory patterns seen as a result of high loop gain which can appear purely obstructive or even missed when viewing in a less compressed window.

[0093] Trap space has been shown to be efficacious in the treatment of CSA in patients with heart failure; with the addition of 400-600 cc of trap space alone resulting in improved sleep quality and respiratory stabilization, without detrimental effect on stroke volume or cardiac index as measured by transthoracic echocardiography, heart rate, or blood pressure. Other data suggest that CO2 modulation via trap space is effective in significantly reducing AHI in

[0094] 18

[0095] MEl\57694243.vl Docket No.: 122295-07320 a majority of OSA patients with a wide range of chemoreflex gains, with improved control over other interventions such as hyperoxia and transient isocapnia. In clinical practice, the main limitations are excessive leak (site or total volume), mask fit (tightness), and amplification of borderline claustrophobia.

[0096] For patients requiring the CO2 gas source, a pressurized canister 2 of medical grade CO2 gas may be utilized; for example, a five-pound steel canister that may be mounted on the side of the PAPGAM rack. The pressure from the canister 2 is regulated to an appropriate delivery value (approximately 10-40 PSIG) by virtue of an adjustable dual indicator mechanical pressure regulator 50 that is attached directly to the outlet 3 of the canister 2. A lever-operated shut-off valve 52 enables manual cut-off of the CO2 supply.

[0097] The use of non-vented masking with EERS is highly reliant on an adequate mask seal, as significant leakage (even 20-30 1pm which is considered acceptable in standard CPAP application) may “wash out” rebreathing space and results in loss of breathing stability depending on the site of leak. Therefore, achieving adequate mask seal is paramount in successful therapy. Patients who demonstrate excessive leak should undergo mask fitting, with consideration of adjuncts such as a chin strap or lip tape to prevent washout through the mouth.

[0098] The system (PAPGAM) is controllable remotely from another computer or workstation via a wireless (or alternatively, wired) TCP / IP connection 110 using the Remote Desktop feature of Windows. A LinkSys USB wireless Ethernet receiver / transmitter may perform this function.

[0099] The PAPGAM system is designed for use principally during a sleep study to determine the appropriate prescription for CO2 gas in conjunction with xPAP therapy for patients suffering from periodic breathing. Although a patient ordinarily is treated as for a

[0100] 19

[0101] MEl\57694243.vl Docket No.: 122295-07320 typical sleep study, such a step may not be necessary given the capabilities of the PAPGAM system.

[0102] PAPGAM CLINICAL: A clinical PAPGAM embodiment is intended for use primarily in a clinical setting, particularly a sleep laboratory. It permits operator adjustment of CO2 and air bleed parameters, can record detailed information, and can output reports in set formats. The unit may have a hand portable or cart form factor (housing) and may be remotely operable.

[0103] PAPGAM HOME: A "home" unit embodiment is intended for a non-clinical setting, such as a patient's home. The home unit is preferably not user adjustable, but can be programmed by a home care technician according to a physician's prescription. It has a simple on / off switch and a number of status indicators. The CO2 source can be incorporated directly into the unit by means of a screw-in type canister or it can be connected via tubing. The canister itself may have an orifice sized to limit flow to a maximum specification. The home unit may incorporate simplified recording and reporting capabilities which are accessible remotely by a clinician, e.g., via a dial-up connection. This unit can have a form factor that is as compact as possible, preferably a bedside tabletop size that fits under the patient's xPAP unit.

[0104] Fig. 2A is a schematic diagram of a variable trap space embodiment in which a mask assembly 705 with tubing 710, 720, 740 as described herein is connected to a modulated positive pressure unit 100 that includes the features of components 110 (port to receive ambient air input), 111 (regulator valve to control air flow), 115 (air filter), 117 (air flow actuator such as fan or blower), 119 (optional heater / humidifier assembly), 140 (mixing chamber), 142 (gas source control valve connected to controller 112), 108 (outflow port 108 that connects to mask tubing 107 and mask connector 105), wherein the controller 112 is further connected to display 102, user control panel 104 having a keyboard and / or softkeys or

[0105] 20

[0106] MEl\57694243.vl Docket No.: 122295-07320 other manual control elements 101 to control device 100 operation. The controller 112 can be connected to a memory 114 for storing data, operating parameters of the device and software configured to operate the device. A battery 120 and power regulation circuit 122 are connected to the controller 112 and other components to provide power as needed. The battery 120 can also include an integrated charger connectable to an external power source at port 124 that can also provide operating power to the device 100 form standard wall outlets. The controller 112 can also be connected to a wireless transmitter and / or receiver 116 having an antenna to enable wireless communication 152 with portable communication device 150 such as a mobile phone or wireless tablet device using an available wireless communication network, a Bluetooth connection or other wireless link. A communications port 109 can also be connected to controller 112 for wired connection to external communication and / or computer networks. These components are located within a single pressure regulator housing 100 that can comprise a hand portable unit weighing less than 10 pounds, or preferably less than 5 pounds.

[0107] An optional gas sensor 715 can be integrated into the mask in one or more of the trap volumes to monitor CO2 levels and can optionally be used to regulate a level delivered to the mask. The sensor can measure gases within an inhalation chamber 709 within the mouth and nose covering that passes air into the mouth and nose along with any supplemental gas flow as described herein during inhalation and also passes exhalation by the user that at least partially enters one or more trap volumes within the mask or attached to the mask. The inhalation chamber forms a portion of the trap volume, but may retain only a small portion of the trapped carbon dioxide at the end of exhalation.

[0108] The single housing can include display 102, such as a touchscreen display to control operation of the unit 100 and also display operating conditions of the unit 100 and show a record of prior use. The unit 100 can also include a user interface 104 such as a control panel

[0109] 21

[0110] MEl\57694243.vl Docket No.: 122295-07320 that controls operations of the unit 100 to dispense pressurized air mixed with CO2 for delivery to the mask through tubing connected at connector 108. Air is drawn into the unit 100 at input aperture 110. The tank or canister 106 is connected by tube 144 to unit 100 at port 124 having a valve 145 connected to controller 112. The controller 112 and memory within unit 100 enables the control of metered amounts of CO2 as described herein. Unit 100 can include both wired and wireless communication ports for remote access and transmission of treatment data logged during use.

[0111] One purpose of this embodiment of the present invention provides the option to raise the CO2 concentration of air being delivered from the device to a target value without the use of supplemental CO2. This is accomplished by causing the patient to rebreathe his own CO2 from a reservoir that can include a plurality of volumes as described herein that are within and / or attached to the mask. The reservoir may, for example, include a length of hose or tubing with a capacity of up to approximately 500 ml depending on the needs of the patient. Ordinarily, no air should leak from hose / mask combination. A seal 708 such as a gasket around the edges of the mask contacting the skin of the patient to provide a gas seal so that exhaled breath can only exit the mask through the tube or tubes connected to the mask.

[0112] The patient's own CO2 is accumulated in this reservoir, so he or she rebreathes it. Thus, as CO2 is rebreathed from the trap volume(s) of the mask assembly, breathing is stabilized using an appropriately sized trap volume. In some embodiments a gas sensor 715 monitors the CO2 level as described herein.

[0113] The concentration of CO2 in the trap space can be on a gradient (highest at the mask, lowest at the interface with the CPAP 12 in Fig. 1, for example). As the patient breathes in the air accumulated in the trap space, the concentration will change. A computational method can be executed by the computer 40 to determine average inspired CO2, so that the desired

[0114] 22

[0115] MEl\57694243.vl Docket No.: 122295-07320 level can be sustained. Note that the user can also employ a pulse oximeter and or ECG sensor 58 to monitor physiological conditions during use.

[0116] Periodic breathing in a patient tends to have a fairly fixed-time component. That is, the actual period of the oscillations is generally determined by physiological conditions that are reasonably fixed in the short term. Hence, any periodic breathing patient tends to have well-defined cycles. The principal determinant is the amount of time that it takes for changes in carbon dioxide levels to be sensed by the brain. The breathing period tends to be about double that time. In most congestive heart failure patients, this results in an apnea-to- apnea period of approximately a minute and a half.

[0117] This embodiment might not include positive airway pressure, and the exact mix of CO2 may not be important. In fact, the delivery mechanism might be as simple as injecting CO2 in high concentrations into a loose-fitting facemask in a manner timed to coincide with the inspiration of a few breaths.

[0118] Fig. 3 is a schematic diagram of a method 500 of stabilizing breathing during sleep according to an embodiment of the present invention. The method 500 may begin at Step 502 by applying continuous positive airway pressure to a sleeping patient while measuring CO2 at a non-leaking mask worn by the patient to determine a loop gain and arousal threshold. In Step 504, the method continues by determining a volume of an expiratory breathing space sufficient to treat hypocapnia condition of the patient. In Step 506, the method continues by adjusting a mask assembly having at least three different volume settings to select at least one volume setting to capture CO2 during sleep periods. In Step 508, the method continues by treating the patient using the mask assembly having the selected volume setting. In the Step 510, the method concludes by measuring a response of the patient to treatment and further adjusting the volume setting to further improve breathing patterns.

[0119] 23

[0120] MEl\57694243.vl Docket No.: 122295-07320

[0121] EERS may be achieved by using a mask without vents or by removing the typical mask exhaust vents. The difference between a ventless mask and a vented mask is described in Fig. 11, for example. This converts a standard “vented” CPAP mask into a “non-vented” mask setup, and adds about 70 (for a nasal mask) to 100 cc’s (for an oronasal mask) of trap space to the system. Additional EERS volumes may then be added by inserting a plurality of flexible tubes totaling 50 cc increments to the mask tubing, for example up to 150 cc’s. This multilumen system shown schematically in Fig, 4 can include features such as a safety flap and / or exhaust ports for one or more lumens. The multilumen configuration serves to reduce the amount of turbulence in a simple tube where the incoming positive airway pressure mixes with exhaled CO2 (see Fig. 5) which diminishes the ability of the user to rebreath the CO2 efficiently.

[0122] Exemplary EERS tubing 210 including a plurality of inner flexible tubes 620 is depicted in Fig. 6. In some embodiments, the tubing 210 may be between nine to twelve centimeters in length and about twenty -two millimeters in diameter. The tubing 210 may be composed of slightly elastic material. The tubing 210 may include multiple flexible tubes 220 to enhance CO2 capture (and thus rebreathing capacity) and also reduce turbulent flow-related blow-off.

[0123] Fig. 7 depicts expansion or billowing of the tubes 220 of Fig. 6. Although Fig. 7 depicts only a few billowed tubes 220, some or all of the tubes 220 can expand during exhalation to capture CO2, for example. During exhalation, the diameter of tubing 220 may increase over twenty -two millimeters in diameter. The length may also increase and the elastic material enables improved rebreathing during return recoil. The tubes act as springs during expansion so that the they apply a compressive force to the captured CO2 that assists with rebreathing by the user. Fig. 8 illustrates a further example wherein at least a portion of the inner tubes 240 can aid in linearized airflow directing pressurized flow from unit 24 (or

[0124] 24

[0125] MEl\57694243.vl Docket No.: 122295-07320

[0126] 100) between the ends of the tube that are separate from the tube space used to retain expired CO2.

[0127] Fig. 9 is a top view of a converted non-vented mask 700 according to an embodiment of the present invention. FIG. 11 is a front view of the mask 700. The mask 700 may be connected to a safety valve 710. The safety valve 710 may be joined to EERS tubing 720 by a connector 730. The safety valve 710 may include internal flaps 712 that remain in a closed position when there is no pressure. The flaps 712 may move to an open position during operation of CPAP. When there is no CPAP pressure, the patient may breathe through side openings 714 in the safety valve 710.

[0128] EERS tubing 720 may include corrugated flexible tubing in 50 cc increments up to 150 cc. In some embodiments, the tubing 720 may be replaced with another tubing 720 having a different increment of tubing, and therefore a different amount of dead space. In other embodiments, the dead space within tubing 720 may be dynamically adjusted during use.

[0129] The swivel valve 740, which allows for continuous venting and thus represents the termination of the non-vented circuit, may be added at the distal end of the EERS tubing 720 and may allow for exhalation of CO2. FIG. 10 depicts the swivel valve 740. In some embodiments, the swivel valve 740 is a Philips Whisper Swivel II Exhalation Valve. In fullface mask embodiments, a safety valve 710 (for example a non -rebreathing valve) may be added to prevent theoretical asphyxiation in the event of a power outage or machine malfunction but could be considered optional in nasal -only embodiments. Most if not all current full-face masks come with an inbuilt non-rebreathing valve, and no added safety valve 710 is required. In some embodiments, safety valves 710 are also employed in nasal masks.

[0130] 25

[0131] MEl\57694243.vl Docket No.: 122295-07320

[0132] In some embodiments, EERS may employ low flow carbogen (fixed O2 / CO2 gas combinations) or CO2. The appropriate low flow gas may be chosen, or automatically adjusted in use, based on detected apneas and hypopnea. An important feature of the current system is a non-intuitive improvement of CO2 trapping and rebreathing by using a multilumen tube, including an expanding volume under tension that behaves like a pump. This preferably provides a mask system that is less leak sensitive. Both multilumen tube configurations and the addition of low concentrations of CO2 make the system less leak sensitive.

[0133] Illustrated in Fig. 12 are recorded data 800 demonstrating an unexpected consequence of using the trap space volume with continuous wash-out with positive airway pressure to provide respiratory control stability in the treatment of sleep apnea. A baseline polysomnography recording 802 shows obstruction with high loop gain features including medium cycle, self-similar waxing and waning of respiratory events where the hypoxia nadir occurs after the peak of respiration in the following cycle indicating a mixing delay. Panel 804 illustrates standard CPAP titration showing no improvement in breathing pattern, whereas panel 806 shows CPAP with selected trapping volume in a nonvented mask that demonstrates stabilized breathing. See Quinn et al; Enhanced expiratory rebreathing space for high loop gain sleep apnea treatment: Frontiers in Sleep; 9 / 2023: DOI 10.3389 / frsle.2023.1248371.

[0134] To measure the level of self-similarity (SS) in effort signals, present waxing and waning oscillations were identified. By connecting consecutive inspiratory and expiratory amplitude peaks, the ventilatory envelope was computed, allowing the identification of local reductions in respiratory inductive plethysmography (RIP) derived effort signals. During sleep, amplitude reductions >30%, or alternatively greater than 20%, or over 40%, with a duration of at least 10 seconds were associated with hypopneic or apneic events. Fig. 13 A

[0135] 26

[0136] MEl\57694243.vl Docket No.: 122295-07320 shows how both a trace with regular breathing and a trace with waxing and waning oscillations are evaluated using their respective envelopes.

[0137] SS scores can be used to generate histograms and a logistic regression computational method can be trained and evaluated using 5-fold cross validation, for example. Other machine learning methods can also be used. Comparison of histograms relative to an entire training group and a group in which treatment has failed can be used for generating an error score for the analysis. The use of both SS scores and loop gain estimates by phenotyping using polysomnography can be analyzed using polynomial fitting and computing a correlation coefficient.

[0138] Areas between effort reductions were identified as oscillations if the distance between the consecutive effort reductions was less than two minutes, ensuring waxing-waning both oscillations with a short (<30 seconds) or long (>60 seconds) cycle time can be captured. To differentiate the self-similar waxing and waning phenotype from reductions in effort related to classic obstructive sleep apnea, envelope segments were only included when meeting both of the following two horizontal symmetry morphology tests, see Fig. 13B.

[0139] Test 1 : The normalized positive (pnOrm) and 180° rotated negative (nnOrm) envelope show a convolution score exceeding a threshold of 0.5. , i.e.: max (P n orm Unarm)

[0140] I > 0.5, where 1 is the segment length and the positive / negative envelope (x) are normalized by: x — meanfx) xnorm = std(x) + le6

[0141] 27

[0142] MEl\57694243.vl Docket No.: 122295-07320

[0143] Test 2: The location of maximum distance between the positive and negative envelope

[0144] (tmax) is <15%, relative to the respective midpoint between the two effort reductions, i.e.:.

[0145] 11=1^ < 0.15, where ti and t2 represent the distance to tmax from the leading and trailing effort reductions, respectively.

[0146] Using a sliding window such as a 3-minute window, for example, chains of three consecutive oscillations exceeding both horizontal symmetry morphology measurements were identified, while ignoring sporadic (likely false positive) oscillations. Posterior to this output smoothing, RIP segments that included three or more oscillation were assessed for SS (high vertical symmetry). Fig. 13C which shows how signal oscillations were marked as expressed high loop gain (HLG) when the maximum envelope convolution score among its 2 two neighboring oscillations (SSy,x,z) exceeds a user-defined threshold ranging from 0-1 (default=0.8), i.e.:

[0147] SSy,x,z = max ((Y * X),(Y * Z))

[0148] For each patient, the diagnostic phase of their sleep recording was cut into five-minute segments. In each segment in which the patient was asleep for at least one minute, the average SS score across all automatically identified oscillations was calculated. Segments without oscillations were set to a score of zero. To summarize the level of SS across the recording, histograms were computed using 10 bins. All histograms were normalized, so that the total of all bins adds up to 100. In each training set the average histogram for both the success group

[0149] 28

[0150] MEl\57694243.vl Docket No.: 122295-07320 and the failure group was calculated by adding all respective histograms together and dividing them by the number of patients within their respective groups.

[0151] Each patient histogram from the test set was compared to both the average histogram from the success and failure group, resulting in two error scores:

[0152] 1. Comparing a patient histogram to the average histogram of all training patients with little to no residual respiratory events.

[0153] 2. Comparing a patient histogram to the average histogram of all training patients that showed significant residual respiratory events.

[0154] The mean absolute error (MAE) was computed using the following equation: n

[0155] MAE = X | hte- htr | i-1 n where n is the number of histogram bars (10), and, hteand htr, represent the histogram of the test patient and the average histogram of the training patients, respectively. The difference between the two error scores was used as the input for the logistic regression model.

[0156] The original SS detector detected central apneas based on reductions in RIP signal and directly computes the level of temporal SS (resemblances in waveform over time) of the excursion envelope. During clinical experimentation we noticed the model lacked the ability to handle small asymmetries in the signals. This algorithmic rigidity caused clinically common variances in consecutive RIP fluctuation to remain undetected. Moreover, brief clusters were frequently missed. The present modified algorithm now implements an essential assessment of the morphology of individual events together with output smoothing to allow a less strict threshold when assessing temporal SS.

[0157] 29

[0158] MEl\57694243.vl Docket No.: 122295-07320

[0159] First, similar to the original model, local reductions in envelope excursion are automatically associated with apneas / hypopneas. Second, intermediate signal envelopes, i.e., possible breathing oscillations, are assessed based on their morphological characteristics. This is done based on the two morphology measurements as described herein. The typical "football" shape oscillatory morphology is identified, regardless of small asymmetries, thereby making the computational process more sensitive in nature compared to the original approach. This improved SS method is more robust in estimating the high loop gain component in the apnea pathophysiology regardless of possible coexisting admixed central and obstructive features. Third, the implemented posterior output smoothing helps restrain the false positive rate of this method. Fourth, only after the smoothing step, temporal similarity was computed.

[0160] The patient data used to train the approach described herein using the logistic regression computational process has utilized the LATAM Sleep Net cohort (International Standard Randomized Controlled Trial Number: 11936746). This dataset was used to compare and characterize SS with loop gain. This cohort is a clinic-based, prospective study of adult women recruited from 18 centers across Latin America (2022-2023), designed to describe the epidemiology of obstructive sleep apnea among Latin American women. To date, a total of 536 women have participated and undergone comprehensive sleep evaluations. Participants who reported any CPAP or other therapy were excluded.

[0161] Illustrated in Fig. 14 is a process sequence 850 for classifying a patient for treatment with the systems and methods described herein. As many patients not suitable for standard CPAP therapy but have conditions that may be treated by self-administration at home or traveling using the systems described herein without the need for being in a sleep clinic, it is more effective to initially evaluate each patient and properly classify their disorder and thereby improve prospects for successful treatment. Although detailed analysis of the

[0162] 30

[0163] MEl\57694243.vl Docket No.: 122295-07320 individual characteristics of each is the most effective method for classification, automated computation methods can be effective in improving the course of diagnosis and treatment. As shown in Fig. 14, this process can include the measurement of breathing cycle 852 of each patient such as by respiratory inductive plethysmography (RIP), for example. An automated analysis 854 as described in connection with Figs 13A-13C can be performed on the acquired data in which self-similarity over a sequence of breathing cycles can be used to quantitatively characterize the condition of the patient. The variance in the peak amplitudes between inspiratory and expiratory periods of the breathing cycle can be compared 856 with a threshold so that variations over 30%, or over 40%, for example, can be used to diagnose the condition of the patient as having high loop gain which can indicate the need for augmented therapy beyond that provided by traditional CPAP. Thus automated diagnostic analysis serves to classify the patient 858 to determine if the positive pressure system described herein using a mask assembly with trapping used to capture expired CO2 can be effective in treatment 860 of the condition of the patient. The process can specifically indicate the proper trapping volume level that will be effective for treatment. The process can also indicate whether the flexible tubing as shown in Fig, 7 will be effective using the elastic characteristics of the tubing to assist the patient with rebreathing of CO2.

[0164] It will be appreciated by those skilled in the art that modifications to, and variations of the above described device and methods can be made without departing from the inventive concepts disclosed herein. Accordingly, the disclosure should not be viewed as limited except as by the scope and spirit of the appended claims.

[0165] For example, given the low effective concentrations of CO2 discovered by Applicant, some embodiments will not employ a gas mixing module 27 of Fig. 1 but rather will achieve the proper combination of PAP (pressurized air) and CO2 in some other means or in the PCVSM subsystem or the like. Respiratory instability may be caused by a variety of

[0166] 31

[0167] MEl\57694243.vl Docket No.: 122295-07320 conditions such as sleep apnea, renal failure, congestive heart failure and other conditions. It is understood from the foregoing discussion hat the present invention is applicable to each of these conditions.

[0168] 32

[0169] MEl\57694243.vl

Claims

Docket No.: 122295-07320Claims1. A face mask to stabilize breathing during sleep comprising: a mask having a trap volume to retain exhaled carbon dioxide for rebreathing by a user, the trap volume comprising a plurality of cavities fluidly coupled to an inhalation chamber of the face mask to treat sleep apnea wherein the cavities retain exhaled carbon dioxide that is returned to the inhalation chamber during a breathing cycle for rebreathing by the user.

2. The face mask of claim 1 wherein the one or more of the cavities are bounded by one or more walls of the face mask.

3. The face mask of claim 1 and / or 2 wherein the face mask is connectable to a positive pressure regulator in a regulator housing assembly that mixes air with carbon dioxide from a source, the regulator housing assembly further comprising: a controller within the regulator housing assembly and connected to a flow actuator to control a flow output from the regulator housing assembly that is coupled to the face mask; and a control panel to control mixing of air with carbon dioxide.

4. The assembly of claim 3 wherein the control panel is configured to actuate mixing at a selected level.

5. The face mask of any one of claims 1 and / or 2, wherein the mask assembly comprises a trap reservoir that includes a tube that houses a plurality of small diameter tubes, one or more of the small diameter tube optionally comprising one of a plurality of cavities..

6. The face mask of any one of claims 1-5, wherein the plurality of cavities are flexible such that they expand and / or contract during a breathing cycle to regulate an amount of retained CO2.

7. The face mask of any one of claims 1-6, wherein retained CO2 from the exhaled breath includes retained CO2 in one or more of the plurality of cavities located within the face mask.33MEl\57694243.vlDocket No.: 122295-073208. The face mask of any one of claims 1-7, wherein the plurality of cavities have a plurality of different volumes configured to retain different amounts of CO2.

9. The face mask of any one of claims 1-8, further comprising a non-rebreathing valve in the face mask.

10. The face mask of any one of claims 1-9, wherein the face mask further comprises an exhalation port connectable to a tube.

11. The face mask of any one of claims 1-10, further comprising a supplemental oxygen source coupled to the face mask.

12. The face mask of any one of claims 1-10, further comprising a supplemental CO2 source, or a combination of O2 and CO2, coupled to the face mask.

13. The face mask of any one of claims 1-10, wherein the face mask is connected to a positive airway pressure system having a continuous operating mode, a bi-level operating mode, and an adaptive operating mode.

14. The face mask of any one of claims 1-13, wherein the face mask is non-vented.

15. The face mask of any one of claims 1-14, wherein the trap volume has a volume in a range of 50 cc to 150 cc.

16. The face mask of any one of claims 1-15, further comprising an actuator or attachment to adjust a size of the trap volume during sleep in response to a measured condition of the user.

17. The face mask of any one of claims 1-16, further comprising a sensor to measure a loop gain of a user and selecting a volume for the reservoir based on the measured loop gain.34MEl\57694243.vlDocket No.: 122295-0732018. The face mask of any one of claims 1-17, further comprising a trap volume attachment connectable to the face mask, the attachment comprising a plurality of connectable tube segments.

19. The face mask of any one of claims 1-18, further comprising a continuous air pressure source configured to deliver an air flow that includes CO2 to the mask assembly.

20. The face mask of claim 3, wherein the assembly generates plethysmography breathing cycle data and further comprising a processor performing automated analysis of the data to classify a condition of the user as requiring the delivery of a positive pressure including CO2 at a level of less than 2%.

21. The face mask of any one of claims 1-20 wherein the trap volume has a volume in a range of 50-75 cc, or in the range of 75-100 cc, or in the range of 100-150 cc.

22. The face mask of any one of claims 1-20 further comprising a fluid impermeable seal that engages the skin of the user.

23. The face mask of any one of claims 1-20 wherein further comprising and airflow path for inhalation and exhalation through a port on the mask.

24. The face mask of any one of claims 23 wherein the port is fluidly coupled to at least one of an oxygen source and a carbon dioxide source.

25. A method for stabilizing breathing during sleep comprising; operating a breathing system at a positive pressure to assist beathing of a user wherein the user wears a mask assembly having a trap, the trap defining a reservoir to retain CO2 from exhaled breath by the user; retaining CO2 from the exhaled breath in the trap, wherein the trap reservoir comprises a plurality of cavities that retains at least a portion of exhaled CO2; and35MEl\57694243.vlDocket No.: 122295-07320 wherein the user inhales at least a portion of the retained CO2 during one or more subsequent breathing cycles.

26. The method of claim 25, wherein the trap reservoir includes the plurality of cavities that are each bounded by one or more walls of the face mask.

27. The method of claims 25 or 26, wherein the trap reservoir further comprises a tube that houses a plurality of small diameter tubes, each small diameter tube comprising one of the plurality of cavities.

28. The method of any one of claims 25-27, wherein during breathing the plurality of cavities expand and contract to regulate an amount of retained CO2.

29. The method of any one of claims 25-28, wherein retaining CO2 from the exhaled breath includes retaining CO2 in one or more of the plurality of cavities in the face mask.

30. The method of any one of claims 25-29, wherein the plurality of cavities have a plurality of different volumes configured to retain different amounts of CO2.

31. The method of any one of claims 25-30, further comprising operating a non- rebreathing valve in the face mask.

32. The method of any one of claims 25-31, wherein the face mask further comprises an exhalation port.

33. The method of any one of claims 25-32, further comprising flowing supplemental oxygen into the face mask.

34. The method of any one of claims 25-33, further comprising flowing supplemental CO2 or a combination of O2 and CO2 into the face mask.

35. The method of any one of claims 25-34, further comprising connecting the face mask to a positive airway pressure system having a continuous operating mode, a bi-level operating mode, and an adaptive operating mode.36MEl\57694243.vlDocket No.: 122295-0732036. The method of any one of claims 25-35, wherein the face mask is non-vented.

37. The method of any one of claims 25-36, wherein the reservoir has a volume in a range of 50 cc to 150 cc.

38. The method of any one of claims 25-37, further comprising adjusting a volume of the reservoir during sleep in response to a measured condition of the user.

39. The method of any one of claims 25-38, further comprising measuring a loop gain of a user and selecting a volume for the reservoir based on the measured loop gain.

40. The method of any one of claims 25-39, further comprising selecting a reservoir volume for the reservoir to be connected to the face mask, the reservoir comprising a plurality of connectable tube segments.

41. The method of any one of claims 25-40, further comprising continuous air pressure source configured to deliver an air flow that includes CO2 to the mask assembly.

42. The method of any one of claims 25-41, further comprising performing plethysmography to measure the breathing cycle of the user to classify a condition of the user for treatment.

43. The method of any one of claims 42, wherein the step of performing plethysmography generates breathing cycle data and further comprising performing automated analysis of the data to classify a condition of the user as requiring the delivery of a positive pressure including CO2 at a level of less than 2%.

44. The method of any one of claims 25-43 wherein the trap reservoir has a volume between 50-75 cc, or between 75-100 cc, or between 100-150 cc, or a combination of reservoir volumes in two more of these ranges.

45. A rebreathing assembly to treat sleep apnea comprising:37MEl\57694243.vlDocket No.: 122295-07320 a mask assembly having a trap volume to retain carbon dioxide for rebreathing by a user; a positive pressure regulator in a regulator housing that mixes air with carbon dioxide from a source; a controller within the regulator housing connected to a flow actuator to control a flow output from the regulator housing that is coupled to the mask assembly; and a control panel to control mixing of air with carbon dioxide.

46. The assembly of claim 45 wherein the control panel is configured to actuate mixing at a selected level.

47. The assembly of any one of claims 45 and / or 46, wherein the mask assembly comprises a trap reservoir that includes a plurality of cavities that are each bounded by one or more walls of the face mask.

48. The assembly of any one of claims 45-47, wherein the trap reservoir further comprises a tube that houses a plurality of small diameter tubes, each small diameter tube comprising one of the plurality of cavities.

49. The assembly of any one of claims 45-48, wherein the plurality of cavities are flexible such that they expand and contract during a breathing cycle to regulate an amount of retained CO2.

50. The assembly of any one of claims 45 and / or 49, wherein retained CO2 from the exhaled breath includes retained CO2 in one or more of the plurality of cavities in the face mask.

51. The assembly of any one of claims 45-47, wherein the plurality of cavities have a plurality of different volumes configured to retain different amounts of CO2.

52. The assembly of any one of claims 45-51, further comprising a non-rebreathing valve in the face mask.

53. The assembly of any one of claims 45-52, wherein the face mask further comprises an exhalation port.38MEl\57694243.vlDocket No.: 122295-0732054. The assembly of any one of claims 45-53, further comprising coupling a supplemental oxygen source to the face mask.

55. The assembly of any one of claims 45-54, further comprising coupling a supplemental CO2 source, or a combination of O2 and CO2, to the face mask.

56. The assembly of any one of claims 45-55, wherein the face mask is connected to a positive airway pressure system having a continuous operating mode, a bi-level operating mode, and an adaptive operating mode.

57. The assembly of any one of claims 45-56, wherein the face mask is non-vented.

58. The assembly of any one of claims 45-57, wherein the reservoir has a volume in a range of 50 cc to 150 cc.

59. The assembly of any one of claims 45-58, further comprising an actuator to adjust a volume of the reservoir during sleep in response to a measured condition of the user.

60. The assembly of any one of claims 45-59 wherein the control panel is positioned on the regulator housing.

61. The assembly of any one of claims 45-60, further comprising a sensor to measure a loop gain of a user and selecting a volume for the reservoir based on the measured loop gain.

62. The assembly of any one of claims 45-61, further comprising selecting a reservoir volume for the reservoir to be connected to the face mask, the reservoir comprising a plurality of connectable tube segments.

63. The assembly of any one of claims 45-62, further comprising a continuous air pressure source configured to deliver an air flow that includes CO2 to the mask assembly.39MEl\57694243.vlDocket No.: 122295-0732064. The assembly of any one of claims 45-63, wherein the controller is configured to perform plethysmography to measure a breathing cycle of the user to classify a condition of the user for treatment.

65. The assembly of any one of claims 45-64, wherein the assembly generates plethysmography breathing cycle data and further comprising a processsor performing automated analysis of the data to classify a condition of the user as requiring the delivery of a positive pressure including CO2 at a level of less than 2%.40MEl\57694243.vl

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