Patent Description:
This relates to the collection of Volatile Organic Compounds in exhaled breath while monitoring patients on breathing assisted ventilators.

It has long been understood that breath contains a wide variety of chemicals that can indicate various metabolic or disease states within the human body. Due to the complexity of breath and the hundreds or thousands of volatile compounds that can be found in the breath at low levels, accurate analyses can generally be done using equipment such as Gas Chromatography / Mass Spectrometry, or GCMS. These instruments are not small, and are not generally mobile. Therefore, GCMS analysis on human breath is generally performed by collecting the sample using either an adsorbent for thermal desorption or solvent extraction, or by using whole air techniques such as Tediar bags or canisters. Solvent extracted sorbents and Tediar bags, however, are generally effective at high PPB to PPM levels, and generally not effective for detecting compounds at sub-PPB levels. Vacuum canisters can allow multiple analyses to be performed as needed, and can be effective when the sample is to be pre-screened or analyzed multiple times. Thermal desorption tubes are generally less expensive than vacuum canisters, but are usually more complicated to perform sampling with because they require sampling pumps to meter in a known volume of sample, and a reliable power source. Canisters are evacuated prior to delivery to the sampling location, so just opening the valve will cause air and VOCs to flow into them. However, collecting a breath sample with canisters can also become more complicated when taking a time weighted average sample over minutes or hours due to the use of flow restrictors or controllers.

<CIT> relates to a replaceable spectroscopic detector used in volatile organic compounds testing devices, such as a portable breath testing device for roadside drug testing or a testing device for any air handling systems, such as those used for indoor agriculture, which reversibly sorb compounds and prepare a concentrated sample in a single gas cell configured for performing spectroscopy of the contents within the cell.

<CIT> relates to a breath condensate sampler for use with a mechanical ventilator, the breath condensate sampler comprises an airflow valve disposed in the expiratory limb of the ventilator, a condensate formation means, and a condensate collection means.

<NPL>, discloses a device for CO2-controlled sampling of alveolar gas in mechanically ventilated patients. The device comprises an electrically operated two-way valve. Adsorption traps containing activated charcoal are mounted onto the two outlets of the valve. By means of a Y piece, the traps are connected to a roller pump working at a constant flow. Volatile substances are collected and concentrated by adsorption onto the activated charcoal.

This relates to the collection of Volatile Organic Compounds in exhaled breath while monitoring patients on breathing assisted ventilators. The concentration and types of VOCs can be used to diagnose disease and infection in the lungs, such as with bacterial infections, as well as providing marker chemicals that can indicate a host of other diseases or infections. In some embodiments, a tube is connected to the outlet line of the ventilator, near a location of the outlet line where the ventilator line connects into the control unit. Upon exhalation, the air remaining in the outlet line can include deep, alveolar air from deep within the lungs that can contain rich levels of VOCs.

As the ventilator unit pressurizes the inlet line during inspiration, both the inlet line and outlet line can pressurize. As a result, the outlet line compresses and pressurizes the previously-exhaled breath remaining in the outlet line. This pressurization can be used to drive a small amount of the compressed exhaled air through an adsorbent by opening a one-way valve to allow air to flow into the adsorbent. In this way, the exhaled air can be sampled without the use of an additional pump other than the ventilator pump that drives the pressurization of the ventilator lines. Approximately <NUM> to <NUM> cc per inhaled breath, or about <NUM> to <NUM> cc/min for an average <NUM> breath cycles per minute, can enter the sample collection device during a sampling process.

A sleeve can be placed around the adsorbent device and an outlet at the end of the adsorbent device can allow air to fill into this sleeve volume after passing through the adsorbent, thereby increasing the amount of air sampled through the adsorbent during each pressurization cycle, for example. The sleeve volume can be coupled to another one-way valve that allows the air to release back into the ventilator line once the VOCs have been extracted.

Sampling for an hour using <NUM> H2O pressure during each pressurization cycle can enable the system to collect between <NUM> to <NUM> cc of air per hour, for example. In some embodiments, this amount is adjustable based on changing the volume added by the outer sleeve or an optional inlet reservoir. Collecting between <NUM> and <NUM> cc of air per hour can allow detection of VOCs down to sub-PPB levels or even down to low part-per-trillion levels if a preconcentration and splitless injection is performed into a GCMS. Hundreds of different VOCs can be monitored to determine levels of infection, levels of various disease markers, and levels of anesthesia in the breath. The device can be easy to implement and use. Hospital staff can unscrew a cap and screw or click the adsorbent onto a tee connector to attach the sampling device to the ventilator line. Thus, hospital staff can perform the sample collection with minimal training and the analysis can be performed in a nearby lab using GC or GCMS.

It has long been desired to reduce the complexity of tube sampling, and one approach has been to use diffusion tubes that will adsorb compounds at a constant rate during the exposure period. Diffusive sampling onto thermal desorption tubes without the need for a pumping mechanism can also collect and enrich VOCs prior to GC or GCMS analysis. Diffusive sampling rates for many VOCs have been determined using diffusive tubes having a <NUM> opening and a depth of <NUM> to the start of the adsorbent bed, such as the tubes described in US EPA Method <NUM>. Unfortunately, diffusive sampling tubes can have a limited range of compounds that they can collect, for example, because the sorbent needs to be strong enough to irreversibly adsorb the compounds of interest at the sampling temperature yet must completely release all compounds during analysis at a desorption temperature that is higher than the sampling temperature. Generally, different adsorbents are used to collect each of C3-C6 compounds, C4-C8 compounds, and C6-C12 compounds using diffusive tubes. Therefore, a simple yet active sampling solution for collection of ventilator air onto a thermal desorption tube is needed to maximize the range of compounds that can be recovered so that a superior solution for monitoring of disease indicating VOCs can be achieved. Such a solution is presented here.

The disclosed system and methods use active sampling onto single or multi-bed adsorbent traps, but are as straightforward as systems and methods that use diffusive tubes, as no costly calibrated pump or power source in addition to the components of the ventilator itself are needed, for example. The disclosed system takes advantage of the accurate regulation of ventilators in use today, which can consistently reproduce pressures and pulse times during each breathing cycle. By actively flowing through the adsorbent, multiple adsorbent beds can be used to capture and release a wider volatility range of VOCs. Increasing or maximizing both sensitivity and recovery of the widest possible volatility range of compounds, which this technique achieves, is important as it is not currently known which chemicals are the most important to monitor.

In some embodiments, sample is collected for a monitoring period of <NUM> minutes to an hour. A shorter period may not allow sampling of a large enough volume to reach required detection limits, for example. Because the pressurization of ventilators is generally about <NUM> H2O (<NUM> mBar), or about <NUM>% of atmospheric pressure, a <NUM>-8cc combined internal volume constitutes about <NUM> - <NUM> cc per inspiration/exhalation cycle. Sampling at slow rates can improve the recovery of chemicals as it allows them to adsorb close to the front of the adsorbent bed. Over a period of <NUM>-<NUM> minutes, a total volume of <NUM>-500cc can be collected, depending on the total internal volume of the sample collection device, which can result in low detection limits. The sample collection device can be heated to a temperature slightly above the patient's body temperature to prevent the relative humidity within the sample collection device from reaching <NUM>%. A low-wattage (e.g., <NUM>-<NUM> watts) heater can heat the sample collection device to avoid condensing conditions. The collection of 200cc or less can allow management of water condensation using the appropriate thermal desorption systems without having to apply gentle heating to the sample collection device, with special attention paid to the construction of the one-way valves (e.g., check valves) to avoid clogging the valves with liquid water if a heater is not used.

<FIG> illustrate exemplary pressurization patterns for ventilators according to some embodiments of the disclosure. Ventilators can operate in several modes of operation. Thus, the operation mode and its corresponding pressurization pattern is taken into account when determining how much sample will pass through the adsorbent device during the sampling period. As long as the average number of cycles per minute is known, the volume collected can be determined by the formula: <MAT> Where P1 is the pressure used during inspiration and P2 is the exhale pressure and Pa is atmospheric pressure. The tube, sleeve, and reservoir and their associated volumes will be described in more detail below with reference to <FIG>.

<FIG> illustrates an exemplary pressurization pattern <NUM> for a ventilator operating in a control mode. In the control mode, breaths are generally initiated by the ventilator. The pressurization pattern <NUM> illustrates the pressure <NUM> of the ventilator lines over time <NUM>. As shown in <FIG>, during inspiration <NUM>, the pressure <NUM> in the ventilator lines rises. After inspiration <NUM> is complete, the pressure <NUM> in the ventilator lines is allowed to decrease. Inspiration <NUM> corresponds with a controlled inhale. After inhalation, the patient exhales as the ventilator pressure is reduced.

<FIG> illustrates an exemplary pressurization pattern <NUM> for a ventilator operating in an assist mode. In the assist mode, breaths are generally initiated by the patient. The pressurization pattern <NUM> illustrates the pressure <NUM> of the ventilator lines over time <NUM>. As shown in <FIG>, during inspiration <NUM>, the pressure <NUM> in the ventilator lines rises. After inspiration <NUM> is complete, the pressure <NUM> in the ventilator lines is allowed to decrease. Inspiration <NUM> corresponds with a controlled inhale. After inhalation, the patient exhales as the ventilator pressure is reduced.

<FIG> illustrate a sample collection system <NUM> according to some embodiments of the disclosure. The sample collection system <NUM> can include a sample collection device <NUM>, a sleeve <NUM>, and caps <NUM> and <NUM>.

The sample collection device can include a sampling inlet <NUM>. The inlet <NUM> can be narrow enough to prevent backward diffusion (e.g., diffusion of compounds from the sorbent to the inlet of the sample collection device) during slow active sampling, and to decrease the component of positive diffusive sampling to nearly zero. As discussed above, <NUM> (<NUM>/<NUM>") TD tubes with a <NUM> opening can sample diffusively at up to <NUM>. 7cc/min, so active sampling at only <NUM>-3cc/min as obtained with <NUM> (<NUM>/<NUM>") TD tubes would include a diffusive component when using standard thermal desorption tube inlet diameters of about <NUM>. With the disclosed approach, the diffusive sampling component is virtually zero because of the narrow inlet diameter. The inlet diameter can be as low as <NUM> (<NUM> inches) and the outer diameter of the cavity <NUM> of the sample collection device <NUM> is in the range of <NUM> to <NUM> (<NUM>/<NUM>" to <NUM>/<NUM>") and the inner diameter of the cavity <NUM> of the sample collection device <NUM> can be less than the outer diameter, such as <NUM> to <NUM> (<NUM>" to <NUM>") (e.g., <NUM> inches or <NUM>).

The sample collection device further includes one or more sorbents <NUM>. The total amount of sorbent used can be in the range of <NUM>-<NUM>, with one to three kinds of sorbents <NUM>. When using multiple kinds of sorbents <NUM> with increasing strength, the sorbents <NUM> can be separated from one another by screens that prevent mixing of the sorbents. For example, the sample collection device includes three sorbent beds 204a, 204b, and 204c to increase the compound volatility range that can be recovered. The total overall length of the sorbent beds <NUM> is around <NUM> to <NUM> (<NUM> to <NUM> inches), with the length of the sample collection device <NUM> being around <NUM> to <NUM> (<NUM> to <NUM> inches). The bed 204a closest to the inlet <NUM> can have the lowest chemical affinity to the one or more target compounds, while the last bed 204c can have the greatest chemical affinity to the one or more target compounds. In other words, the sorbent bed 204a closest to the inlet <NUM> is the "weak" or "weakest" sorbent while the sorbent bed 204c furthest from the inlet <NUM> is the "strong" or "strongest" sorbent. In some examples, the sample collection device <NUM> includes another sorbent bed 204b between the weak sorbent bed 204a and the strong sorbent bed 204c that can have a chemical affinity for the one or more target compounds that is between the chemical affinities of the other sorbent beds 204a and 204c. As an example, the first sorbent bed 204a includes <NUM>-<NUM><NUM>/g of Tenax, Tenax TA, Carbopack C or a similar sorbent, the second sorbent bed 204b includes <NUM>-<NUM><NUM>/g of Tenax TA, Carbopack B or a similar sorbent, and the third sorbent bed 204c includes <NUM>-<NUM><NUM>/g of Carbopack X, Carboxen <NUM>, Carbon Molecular Sieves, or a similar sorbent. Carbopack C, B, X, and Carboxen <NUM> are registered trademarks of Supelco (now Sigma Aldrich/Millipore) in Pennsylvania, United States of America. During analysis, the cavity <NUM> of the sample collection device <NUM> can be heated and back flushed to prevent the heavy compounds from reaching the strong sorbent 204c or sorbents (e.g., compounds trapped in sorbent bed 204a do not reach sorbent bed 204b or sorbent bed 204c).

The sample collection device <NUM> can include a retaining frit <NUM>. The retaining frit <NUM> retains the sorbent beds <NUM> in place. It can be advantageous for the sorbents <NUM> to remain proximate to the opening <NUM> of the sample collection device <NUM>, thus the retaining frit <NUM> can be used to retain the sorbents in the position illustrated. By positioning the sorbents <NUM> away from external seals <NUM>, the sorbents <NUM> can be heated to a high desorption temperature during desorption while a heat sink (not shown) placed near the external seals <NUM> can prevent the seals from being damaged due to the high heat.

The sample collection device includes an internal volume <NUM>. Volume <NUM> is the space in cavity <NUM> not occupied by the sorbent <NUM>. Volume <NUM> can be either filled with an inert material such as glass beads, a glass rod, or other inert, low thermal conducting material, or kept open to maximize the unoccupied volume. Volume <NUM> can create space between the sorbent and the seals, which can be advantageous for the reasons discussed above. During sampling, as will be described in more detail below, the volume <NUM> can hold air that has passed through the sorbent <NUM>. Increasing the internal volume of the sample collection system <NUM> can increase the volume of air that can be sampled during a sampling period of known duration (e.g., an hour).

The sample collection device further includes a port <NUM>. The port <NUM> can be located between two of the external seals 210a and 210b (e.g., the port is between the two lowest of three seals). During sampling, the port <NUM> allows gas that has passed through the adsorbent to exit the cavity <NUM> of the sample collection device <NUM> and flow into the inside <NUM> of the outer sleeve <NUM>, as will be described in more detail below. During analysis, the port <NUM> is used to supply a carrier fluid (e.g., a carrier gas) to back desorb the sorbent <NUM> during GC or GCMS analysis. The seals <NUM> isolate the tube during the travel, such as between the sample collection site (e.g., the ventilator) and the sample analysis site (e.g., a lab). It also prevents leakage during pressurization. Sample collection device <NUM> further includes an internal seal <NUM> and valve <NUM> that seal a top opening <NUM> during sample collection, transport, and desorption. During sampling, a pressure sensor (not shown) or a balloon (see <FIG>) or other elastic, expandable device can be attached to the sample collection device <NUM> at the valve <NUM> end to indicate the change in pressure in the sample collection device <NUM>, which indicates that sampling is occurring. In some embodiments, sample collection device <NUM> does not include internal seal <NUM>, valve <NUM>, and top opening <NUM> and instead is closed at the top.

The sleeve <NUM> can function to isolate the sample collection device <NUM> when the sample collection device <NUM> is not in use. The sleeve <NUM> includes an internal volume <NUM>, threads <NUM> and threads <NUM>. The sample collection device <NUM> can be placed into sleeve <NUM>, and cap <NUM> screws down onto the sleeve <NUM> at threads <NUM> to retain the sample collection device <NUM> within the sleeve <NUM> until returned to the lab. Cap <NUM> includes threads <NUM> that couple to the threads <NUM> of the sleeve and an opening <NUM> that allows the top part of the sample collection device <NUM> to pass through the cap <NUM> when the cap <NUM> and sleeve <NUM> are assembled, as shown in <FIG>.

During sampling, the port <NUM> of the sample collection device <NUM> is open to the internal volume <NUM> of the sleeve <NUM>, as will be described in more detail below. When the sample collection device <NUM> is not in use, isolation cap <NUM> can be screwed on to the sleeve <NUM> at threads <NUM> to keep the sorbent <NUM> isolated both before and after sampling. Isolation cap <NUM> includes threads <NUM>, external seal <NUM>, and internal seal <NUM>. Threads <NUM> can be coupled to the threads <NUM> of sleeve <NUM>. External seal <NUM> forms a seal between the isolation cap <NUM> and the sleeve <NUM> when the isolation cap <NUM> is attached to the sleeve <NUM>. Internal seal <NUM> provides additional sealing of the inlet <NUM> of the sample collection device <NUM>.

<FIG> illustrates the sample collection system <NUM> with the sample collection device <NUM> fully isolated from its external environment. As shown in <FIG>, cap <NUM> can be screwed onto sleeve <NUM> at one end of the sample collection device <NUM> and cap <NUM> can be screwed onto sleeve <NUM> at the other end of the sample collection device <NUM>. When assembled in this way, cap <NUM> is fitted around the sample collection device <NUM>. The sorbent <NUM> of the sample collection device <NUM> is sealed from the external environment by the caps <NUM> and <NUM> and internal seal <NUM>.

<FIG> illustrate coupling <NUM> that connects the sample collection device <NUM> to the ventilator outlet line according to some embodiments of the disclosure. The coupling <NUM> includes an intake one-way valve <NUM> and an outlet one-way valve <NUM> (e.g., check valves). Thus, coupling <NUM> is a valve system. During sampling, the sample collection device <NUM> is connected to coupling <NUM> which connects to the ventilator outlet line at tee <NUM>. The pressure differential rating of the one-way valves <NUM>-<NUM> can be set by the ventilator and/or the patient's needs or tolerances. The pressure differential of the ventilator cycle can be around <NUM>-<NUM> hPa (e.g., <NUM>-<NUM> H2O, <NUM>-<NUM> psi). The one-way valve <NUM> can therefore open when the pressure differential from the ventilator outlet line into the sampler is a positive <NUM> to <NUM> hPa (<NUM> to <NUM> psi), while the one-way valve <NUM> can open when the pressure is greater in the sampler relative to the ventilator outlet line by <NUM> to <NUM> hPa (<NUM>-<NUM> psi) between inspiration pulses.

During inhalation, air from the ventilator output line can flow into the sample collection device <NUM> through the intake one-way valve <NUM> of the coupling <NUM>. Intake one-way valve <NUM> can allow selective opening and closing of inlet <NUM> of the coupling <NUM>. The pressure in the ventilator outlet line, which is higher than the pressure in the sample collection device <NUM> during inhalation, can cause the intake one-way valve <NUM> to open. Once inside the sample collection system <NUM>, the air can then flow through the sorbent <NUM> of the sample collection device <NUM>, allowing the sorbent <NUM> to adsorb or absorb one or more VOCs present in the exhaled breath.

During exhalation, the air that has passed through the sorbent <NUM> can flow through the volume <NUM> of the sleeve <NUM> and back into the ventilator output line (e.g., through tee <NUM>) through the outlet one-way valve <NUM> of the coupling. Outlet one-way valve <NUM> can allow selective opening and closing of the outlet <NUM> of the coupling <NUM>. The pressure in the sample collection system <NUM>, which is higher than the pressure in the sample collection device <NUM> during exhalation, can cause the outlet one-way valve <NUM> to open. Additional details of the sampling process and the airflow into and out of the sample collection device <NUM> will be described below.

<FIG> illustrate the sample collection system <NUM> coupled to the ventilator outlet line according to some embodiments of the disclosure. In some examples, the sample collection device <NUM> can be received by the hospital in the sleeve and cap assembly illustrated in <FIG>. <FIG> illustrates the sample collection device without a cap isolating the inlet <NUM> of the sample collection device <NUM>. <FIG> also includes the coupling <NUM> for fitting the sample collection device to the ventilator outlet line via tee <NUM>. The coupling <NUM> is sized to fit the inlet end of the sample collection device <NUM>, enabling the sample collection device <NUM> to collect a sample from the ventilator outlet line once the sample collection device <NUM> is fitted into the coupling <NUM>. The sample collection device <NUM> and the coupling <NUM> can be threadingly coupled.

<FIG> illustrates the sample collection device <NUM> coupled to the ventilator line by way of coupling <NUM> and tee <NUM>. When the sample collection device <NUM> is connected to the coupling <NUM>, sampling can begin. When sampling is done, the process is reversed by unscrewing the sample collection device <NUM>, replacing the isolation cap <NUM>, and then returning the sample collection device <NUM> in its cap and sleeve assembly to the laboratory for analysis.

<FIG> illustrate the flow of air in the sample collection system <NUM> during a sampling process according to some embodiments of the disclosure. <FIG> illustrates airflow while inspiration (e.g., inhalation) is occurring, and the pressure is increasing by <NUM> to <NUM> H2O relative to expiration (e.g., exhalation), typically. The gas that is pressurized into the outlet line, and tee <NUM>, is the deep alveolar air left from the end of the previous exhalation. As the pressure increases, the intake one-way valve <NUM> of coupling <NUM> allows flow into the inlet <NUM> of the sample collection device <NUM> and through the sorbent <NUM>. VOCs are collected by the sorbent <NUM>, and the air, which is not retained by the sorbent <NUM>, continues through the sample collection device <NUM> where it reaches the port <NUM>. The air continues to flow through the port <NUM> to the outside of the sample collection device <NUM> where it is now confined by the volume <NUM> of the outer sleeve <NUM>. The gas continues to pressurize the rest of the volume down to the outlet one-way valve <NUM> of the coupling <NUM>. However, while the pressure of the ventilator outlet line is pressurized during inspiration, the one way valve <NUM> does not allow flow out of the sample collection system <NUM>, as the pressure is greater in the ventilator line than inside the sleeve <NUM>.

<FIG> illustrates airflow through the sample collection system <NUM> during the exhalation stage of the cycle. The exhalation stage of the cycle is typically longer than the inspiration or pressurization stage. During exhalation, the pressure is higher inside the sample collection device <NUM> and its sleeve <NUM>, so no flow can occur through the inlet one-way valve <NUM>. Instead, the gases are drawn out through the back of the sample collection device <NUM> and into the outer sleeve <NUM> where it ultimately passes through the outlet one-way valve <NUM> and back into the ventilator outlet line through tee <NUM>. Thus, air from the ventilator outlet line is drawn into and through the sample collection device <NUM> and, after sampling has occurred, back into the ventilator outlet line through tee <NUM> using the pressure cycle of the ventilator outlet line. The sample collection device <NUM> is able to collect the sample without including a pump that is separate from the pump included in the ventilator. The consistency of the ventilator and its ability to maintain a record of average cycles per minute, and often the number of total cycles during some monitoring period, allows this sampling strategy to be reliable and repeatable. When samples are not being collected, a blank sample collection device or a plug can be attached to coupling <NUM> to seal the ventilator outlet line. Alternatively, a sealing plunger/o-ring in the tee coupling can create an automatic seal upon removal of the sampling tube.

<FIG> illustrates a chart of the change in pressure <NUM> in the ventilator outlet line and the flow rate <NUM> of air into the sample collection device <NUM> during sampling over time <NUM> as illustrated in <FIG>. The pressure <NUM> in the ventilator outlet line increases during inspiration <NUM> and decreases during exhalation. During inspiration <NUM>, flow into the sample collection device <NUM> occurs. Flow into the sample collection device <NUM> can occur during a period of time that is not as long as the ventilator inspiration stage <NUM>, considering the limited volume of sample collection device <NUM>. For ease of illustration, chart <NUM> includes indication of flow into the sample collection device <NUM> (e.g., illustrated in <FIG>) but does not include negative flow out of the sample collection device <NUM> (e.g., illustrated in <FIG>).

<FIG> illustrate airflow of another sample collection system during sampling according to some embodiments of the disclosure. Sample collection system includes the same components as the sample collection system described above with reference to <FIG>, with some exceptions noted here. Sample collection system includes a modified coupling <NUM> that includes a coupling to a reservoir <NUM>. The reservoir has a volume of <NUM> to <NUM> cc (e.g., <NUM> to <NUM> cc). The coupling <NUM> to the reservoir <NUM> includes threads <NUM> around an opening at which to attach the reservoir <NUM> and a seal <NUM> to seal the connection between the coupling <NUM> and the reservoir <NUM>. Coupling <NUM> further includes an additional seal <NUM> to seal the opening of sleeve <NUM> from the reservoir <NUM>.

As shown in <FIG>, when the inspiration pulse occurs, the reservoir <NUM> fills with air that enters the sample collection system <NUM>. The reservoir <NUM> can fill at a higher rate than the cavity <NUM> of sample collection device <NUM> because there is no sorbent impeding the flow into the reservoir <NUM>, as there is in the case of flow into the cavity <NUM> of sample collection device <NUM> (e.g., sorbent <NUM>).

As shown in <FIG>, after pressurization (e.g., during exhalation), the air can exit the reservoir <NUM> and flow through the adsorbent <NUM> and out the outlet one-way valve <NUM>. In some embodiments, a restriction may be used at outlet <NUM> instead of a one-way valve <NUM>. Since the recovery time is generally <NUM>-<NUM> times longer than the inspiration time, rapid filling of the reservoir <NUM> must be accomplished, but then flow through the adsorbent <NUM> may occur over that period where the pressure of the ventilator line is less than that of the reservoir <NUM> and sample collection device <NUM> assembly. Having one less valve may improve the long term reliability of the sample collection system <NUM>. In this mode, having the assembly vertical or nearly vertical may allow any return spring in the outlet one-way valve <NUM> to be eliminated, just relying on gravity to close a ball against an o-ring, or some other light material over a port, for example. When samples are not being collected, a blank sample collection device or a plug can be attached to coupling <NUM> to seal the ventilator outlet line, or a plunger o-ring combination can automatically close the tee coupling when the sampling device <NUM> is removed.

<FIG> illustrates a chart of the change in pressure <NUM> in the ventilator outlet line and the flow rate <NUM> of air into the sample collection device <NUM> during sampling over time <NUM> as illustrated in <FIG>. The pressure <NUM> in the ventilator outlet line increases during inspiration <NUM> and decreases during exhalation. During inspiration <NUM>, flow into the sample collection device <NUM> occurs. Flow into the sample collection device <NUM> can occur during a period of time that does not fully overlap with the ventilator inspiration stage <NUM> (e.g., flow into the sample collection device <NUM> can continue to occur after inspiration <NUM> has ceased). For ease of illustration, chart <NUM> includes indication of flow into the sample collection device <NUM> (e.g., illustrated in <FIG>) but does not include negative flow out of the sample collection device <NUM> (e.g., illustrated in <FIG>).

<FIG> illustrate another sample collection system according to some embodiments of the disclosure. The sample collection system includes the same components as the sample collection system illustrated in <FIG> and further includes a balloon <NUM> attached to the sample collection device <NUM>. The balloon <NUM> is attached with a clip that opens the valve <NUM> of the sample collection device <NUM>. During sampling, the balloon can be inflated and deflated to accommodate a larger volume of air inside the sample collection system than what is possible without the balloon (e.g., using the system shown in <FIG>). The inclusion of the balloon can also indicate that flow is occurring into and out of the sample collection device <NUM> as expected during sampling. As shown in <FIG>, during inspiration, the balloon <NUM> is able to inflate slightly due to the increased pressure in the sample collection system. As shown in <FIG>, during exhalation, the balloon <NUM> is able to deflate slightly due to the decreased pressure in the sample collection system. After sampling is concluded, the balloon can be discarded and a new balloon can be attached for each use of the sample collection system. When samples are not being collected, a blank sample collection device or a plug can be attached to coupling <NUM> to seal the ventilator outlet line.

<FIG> illustrates a process for collecting a sample according to some embodiments of the disclosure. One or more of the systems illustrated in <FIG> can be used to perform some or all of the steps of process <NUM> to collect a sample of target compounds (e.g., VOCs) from exhaled breath in a ventilator outlet line. Process <NUM> includes a setup process <NUM>, a sampling process <NUM>, and a post-sampling process <NUM>.

Setup process <NUM> includes steps <NUM> and <NUM>. At step <NUM> of process <NUM>, the valve system (e.g., valve system of coupling <NUM>) is coupled to the ventilator outlet line. As shown in <FIG>, the coupling <NUM> can be attached to a tee <NUM> that is connected to the ventilator outlet line. Coupling includes an intake one-way valve <NUM> and an outlet one-way valve <NUM>, as described above.

At step <NUM> of process <NUM>, the sample collection device <NUM> is coupled to the valve system (e.g., valve system of coupling <NUM>). Once steps <NUM> and <NUM>, which can be performed in any order, are complete, the sample collection device <NUM> is also coupled to the ventilator outlet line through the valve system of the coupling <NUM>.

While the ventilator is running, a pump included in the ventilator drives the pressure in the inlet and outlet lines of the ventilator. For example, the pump can generate a pressure pattern according to <FIG>, <FIG>, or <FIG>. During each inspiration pulse, pressure in the ventilator lines increases. Between inspiration pulses, pressure in the ventilator outlet lines decreases. The pressure cycle generated by the ventilator pump drives the flow of air into and out of the sample collection device <NUM> during steps <NUM> and <NUM>, described below.

Sampling process <NUM> includes steps <NUM>, <NUM>, and <NUM>. In step <NUM>, an inspiration pulse occurs and air flows into the sample collection system <NUM> through the intake one-way valve <NUM> of the coupling <NUM>. The flow into the sample collection system <NUM> is driven by the pressure difference between the ventilator outlet line, which can have an elevated pressure during inspiration, and the sample collection system <NUM>. In some embodiments, such as in embodiments which include a side reservoir <NUM> that can hold exhaled air, flow into the sample collection system can continue after the inspiration pulse has ceased, as illustrated in <FIG>.

In step <NUM> of process <NUM>, one or more compounds of interest (e.g., VOCs) present in the exhaled air can be collected in the sorbent <NUM> of the sample collection device <NUM>. In some embodiments, such as in embodiments that do not include the optional side reservoir <NUM>, collection occurs during the inspiration pulse. In some embodiments, such as in embodiments that include the optional side reservoir <NUM>, collection occurs between inspiration pulses.

In step <NUM>, which occurs between inspiration pulses of the ventilator inspiration cycle, air flows out of the sample collection device <NUM> and back into the ventilator outlet line. The air flows through the outlet one-way valve <NUM> of the coupling. The air that flows out of the sample collection system <NUM> has already flowed through the sorbent <NUM> of the sample collection system <NUM>. Thus, air that returns to the ventilator outlet line has already been sampled.

Post-sampling process <NUM> includes steps <NUM> and <NUM>. In step <NUM>, the sample collection device <NUM> is removed from the coupling <NUM> or <NUM>. The sample collection device <NUM> is removed from the coupling <NUM> or <NUM> after a sampling period that can last <NUM> to <NUM> minutes. After the sample collection device <NUM> is removed, it can be placed in the cap-and-sleeve assembly including caps <NUM> and <NUM> and sleeve <NUM>, such as in <FIG>. Isolating the sample collection device <NUM> in this way prevents the sample from becoming contaminated by the environment external to the sorbent <NUM> of the sample collection device <NUM>.

In step <NUM>, a new sample collection device <NUM> is inserted into the coupling <NUM> or <NUM> or a cap or plug is applied to the coupling <NUM> or <NUM>. A new sample collection device <NUM> can be used to collect another sample from the ventilator outlet line. A cap or plug can close the ventilator system when sample collection is not occurring.

The flow rate and flow volume through the sample collection device <NUM> for each breathing cycle depends on the volume between inlet one-way valve <NUM> and the outlet one-way valve <NUM>. The larger that volume, the greater the volume sampled, and therefore, the greater the flow rate. The pressure change during a ventilator breath cycle is on the order of <NUM>-<NUM> H2O. As an example, suppose the pressure change during an exemplary ventilator breath cycle is <NUM> H20, which is about <NUM> atmospheres. As an example, the sample collection device <NUM> is coupled to a 50cc reservoir <NUM>. Under these exemplary conditions, the volume of sample collected is <NUM>. 6cc/breath. With <NUM> breath cycles per minute under these exemplary conditions, sampling occurs at a rate of <NUM> cc/min, resulting in 216cc of air sampled in <NUM> minutes. Detecting pneumonia based on VOC levels in the lungs, for example, can be done by sampling at least 50cc of air and analyzing the sample. Therefore, one way to use the disclosed system is to sample a volume of 10cc - 100cc of air over the course of about <NUM> minutes. Without the optional reservoir <NUM>, sampling times could be longer, but in some cases, that may be desirable. In general, the sampling flow rates can be on the order of <NUM>-15cc/min when using a reservoir <NUM> with a volume in the range of <NUM>-100cc.

<FIG> illustrates a system block diagram <NUM> according to some embodiments of the disclosure. The block diagram <NUM> includes ventilator pump <NUM>, ventilator inlet line <NUM>, the patient <NUM>, ventilator outlet line <NUM>, ventilator outlet vent <NUM> a valve system <NUM> including inlet one-way valve <NUM> and outlet one-way valve <NUM>, the sample collection device <NUM> including a sorbent <NUM>, and optional reservoir <NUM>. As described above, sorbent <NUM> can include a plurality of sorbents (e.g., three sorbents) arranged in order of increasing strength. The valve system <NUM> can be included in coupling <NUM> or <NUM>.

Block diagram <NUM> illustrates a ventilator system <NUM> that includes ventilator pump <NUM>, ventilator outlet vent <NUM> that can open and close, ventilator inlet line <NUM>, ventilator outlet line <NUM>, a valve system <NUM> including inlet one-way valve <NUM> and outlet one-way valve <NUM>, the sample collection device <NUM> including a sorbent <NUM>, and optional reservoir <NUM>. Additional or alternate components, such as timers, sensors, pressure regulators, and control valves, can be included in the system <NUM> without departing from the scope of the disclosure. The block diagram <NUM> also illustrates a sample collection system that includes a valve system <NUM> including inlet one-way valve <NUM> and outlet one-way valve <NUM>, the sample collection device <NUM> including a sorbent <NUM>, and optional reservoir <NUM>.

Ventilator inlet line <NUM> can facilitate flow of gas from the ventilator pump <NUM> into the patient <NUM> (e.g., and into the patient's lungs to support the patient's breathing). The patient <NUM> is also fluidly coupled to the ventilator outlet line <NUM>. The ventilator outlet line <NUM> can facilitate flow of gas from the patient <NUM> to the ventilator outlet vent <NUM>. Because the ventilator inlet line <NUM>, ventilator outlet line <NUM>, and the patient1008 are in fluid communication with one another, when the pressure of the ventilator inlet line <NUM> is increased by the ventilator pump <NUM>, the pressure in the ventilator outlet line <NUM> also increases. The periodic increase of pressure in the ventilator outlet line <NUM>, which is driven by the ventilator pump <NUM>, drives the flow of gas into the sample collection system <NUM>, while the reduction in pressure in between inspiration pulses allows the return of the extracted breath sample into the exhaust line for ultimate delivery to the ventilator vent <NUM>, leaving the VOCs trapped on the sampler adsorbent. Ventilator outlet vent <NUM> can be a valve or a similar mechanism that opens between inspiration pulses driven by the ventilator pump <NUM> and closes during the inspiration pulses. In this way, pressure is allowed to decrease in the ventilator inlet line <NUM>, the ventilator outlet line <NUM>, and the patient <NUM> between inspiration pulses, during exhalation. In some embodiments, alternative means of decreasing the pressure in the ventilator system between inspiration pulses are possible without departing from the scope of the disclosure.

Therefore, according to the above, some embodiments of the disclosure are directed to a ventilator diagnostic VOC sample collection system comprising: a sample collection device, the sample collection device including a cavity containing one or more sorbents; and a valve system coupled to an opening of the cavity of the sample collection system, the valve system comprising a first one-way valve that allows flow of gas into the sample collection system and a second one-way valve that allows flow of gas out of the sample collection system, wherein: the valve system is configured to be coupled to a ventilator outlet line, the sample collection system is configured to allow the flow of gas into the sample collection system to occur during periodic inspiration pulses of an inspiration cycle of the ventilator, the sample collection system is configured to allow the flow of gas out of the sample collection system to occur between the inspiration pulses of the inspiration cycle of the ventilator, a pump of the ventilator increases pressure in the ventilator outlet line during the inspiration pulses of the ventilator, the flow of gas into the sample collection system is actuated by the pump of the ventilator that is coupled to the sample collection system by way of the ventilator outlet line, and the flow of gas out of the sample collection system is facilitated by an outlet valve of the ventilator. Additionally or alternatively, in some embodiments, the ventilator diagnostic VOC sample collection system further includes: a sleeve having a volume, wherein the sleeve is configured to accommodate the sample collection device and configured to be coupled to the valve system. Additionally or alternatively, in some embodiments, the volume of the sleeve includes a fluid conveyance from a port of the sample collection device to the second one-way valve of the valve system, wherein: a distance between the one or more sorbents and the opening of the cavity of the sample collection system is less than a distance between the port and the opening of the cavity of the sample collection system. Additionally or alternatively, in some embodiments, the ventilator diagnostic VOC sample collection system further includes: a reservoir fluidly coupled to the first one-way valve of the valve system and the opening of the cavity of the sample collection device. Additionally or alternatively, in some embodiments, the sample collection system is further configured to: allow the flow of gas into the reservoir during the inspiration pulses; and allow the flow of gas out of the reservoir and into the sample collection device between the inspiration pulses. Additionally or alternatively, in some embodiments, the sample extraction system does not include a pump other than the pump of the ventilator. Additionally or alternatively, in some embodiments, the gas is exhaled air. Additionally or alternatively, in some embodiments, the ventilator diagnostic VOC sample collection system further includes a sampling indicator, wherein the sampling indicator is one of a balloon, a diaphragm, a switch, a pressure gauge, or a pressure sensor.

Some embodiments of the disclosure are directed to a ventilator system comprising: an outlet line; and a pump configured to increase pressure in the outlet line of the ventilator during periodic inspiration pulses of an inspiration cycle of the ventilator; and a sample collection system comprising: a sample collection device, the sample collection device including a cavity containing one or more sorbents; and a valve system coupled to an opening of the cavity of the sample collection system, the valve system comprising a first one-way valve that allows flow of gas into the sample collection system and a second one-way valve that allows flow of gas out of the sample collection system, wherein: the valve system is configured to be coupled to the ventilator outlet line, the sample collection system is configured to allow the flow of gas into the sample collection system to occur during the periodic inspiration pulses of the inspiration cycle of the ventilator, the sample collection system is configured to allow the flow of gas out of the sample collection system to occur between the inspiration pulses of the inspiration cycle of the ventilator, the flow of gas into the sample collection system is actuated by the pump of the ventilator that is coupled to the sample collection system by way of the ventilator outlet line, and the flow of gas out of the sample collection system is facilitated by an outlet valve of the ventilator. Additionally or alternatively, in some embodiments, the ventilator system of claim further comprises: a sleeve having a volume, wherein the sleeve is configured to accommodate the sample collection device and configured to be coupled to the valve system. Additionally or alternatively, in some embodiments, the volume of the sleeve includes a fluid conveyance from a port of the sample collection device to the second one-way valve of the valve system, wherein: a distance between the one or more sorbents and the opening of the cavity of the sample collection system is less than a distance between the port and the opening of the cavity of the sample collection system. Additionally or alternatively, in some embodiments, the ventilator system of claim <NUM>, further comprising: a reservoir fluidly coupled to the first one-way valve of the valve system and the opening of the cavity of the sample collection device. Additionally or alternatively, in some embodiments, the sample collection system is further configured to: allow the flow of gas into the reservoir during the inspiration pulses; and allow the flow of gas out of the reservoir and into the sample collection device between the inspiration pulses. Additionally or alternatively, in some embodiments, the sample extraction system does not include a pump other than the pump of the ventilator. Additionally or alternatively, in some embodiments, the gas is exhaled air. Additionally or alternatively, in some embodiments, the ventilator system further includes a sampling indicator, wherein the sampling indicator is one of a balloon, a diaphragm, a switch, a pressure gauge, or a pressure sensor.

In some embodiments, a method comprises: increasing, with a pump of a ventilator that is fluidly coupled to an outlet line of the ventilator, pressure in the outlet line of the ventilator during periodic inspiration pulses of an inspiration cycle of the ventilator; during the periodic inspiration pulses of the inspiration cycle of the ventilator, actuating, with the pump of the ventilator, the flow of gas into a sample collection system; and between the periodic inspiration pulses of the inspiration cycle of the ventilator, facilitating, with an outlet valve of the ventilator, the flow of gas out of the sample collection system, wherein: the sample collection system is fluidly coupled to a valve system, the valve system is fluidly coupled to the outlet line of the ventilator, the sample collection device comprises a cavity containing one or more sorbents, and the valve system comprises a first one-way valve that allows flow of gas into the sample collection system and a second one-way valve that allows flow of gas out of the sample collection system. Additionally or alternatively, in some embodiments, the sample collection system further comprises a sleeve having a volume, wherein the sleeve is configured to accommodate the sample collection device and configured to be coupled to the valve system. Additionally or alternatively, in some embodiments, the volume of the sleeve includes a fluid conveyance from a port of the sample collection device to the second one-way valve of the valve system, wherein: a distance between the one or more sorbents and the opening of the cavity of the sample collection system is less than a distance between the port and the opening of the cavity of the sample collection system. Additionally or alternatively, in some embodiments, the sample collection system further comprises a reservoir fluidly coupled to the first one-way valve of the valve system and the opening of the cavity of the sample collection device. Additionally or alternatively, in some embodiments, the sample collection system configured to: allow the flow of gas into the reservoir during the inspiration pulses; and allow the flow of gas out of the reservoir and into the sample collection device between the inspiration pulses. Additionally or alternatively, in some embodiments, the sample extraction system does not include a pump other than the pump of the ventilator. Additionally or alternatively, in some embodiments, the gas is exhaled air. Additionally or alternatively, in some embodiments, the method further includes indicating, with a sampling indicator, a change in pressure in the sample collection system, wherein the sampling indicator is one of a balloon, a diaphragm, a switch, a pressure gauge, or a pressure sensor.

Claim 1:
A ventilator system comprising:
an outlet line (<NUM>);
a pump (<NUM>) configured to increase pressure in the outlet line of the ventilator during periodic inspiration pulses of an inspiration cycle of the ventilator; and
a ventilator diagnostic Volatile Organic Compounds, VOC, sample collection system (<NUM>) comprising:
a sample collection device (<NUM>), the sample collection device including a cavity containing one or more sorbents (<NUM>); and
a valve system coupled to an opening of the cavity of the sample collection system, the valve system comprising a first one-way valve (<NUM>) that allows flow of gas into the sample collection system and a second one-way valve (<NUM>) that allows flow of gas out of the sample collection system, wherein:
the valve system is configured to be coupled to the ventilator outlet line,
the sample collection system is configured to allow the flow of gas into the sample collection system via the first one-way valve to occur during periodic inspiration pulses of an inspiration cycle of a ventilator,
the sample collection system is configured to allow the flow of gas out of the sample collection system and into the ventilator outlet line via the second one-way valve to occur between the periodic inspiration pulses of the inspiration cycle of the ventilator,
a pump of the ventilator increases pressure in the ventilator outlet line during the periodic inspiration pulses of the ventilator,
the flow of gas into the sample collection system is actuated by the pump of the ventilator that is coupled to the sample collection system by way of the ventilator outlet line, and
the flow of gas out of the sample collection system is facilitated by an outlet valve of the ventilator.