CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No.

62/639,479, filed March 6, 2018, entitled“VENTILATOR-COUPLED SAMPLE

COLLECTION AND CHEMICAL ANALYSIS DEVICE AND METHOD,” the content of which is hereby incorporated by reference for all purposes.

FIELD OF THE DISCLOSURE

[0002] This relates to the collection of Volatile Organic Compounds in exhaled breath while monitoring patients on breathing assisted ventilators.

BACKGROUND

[0003] 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 Tedlar bags or canisters. Solvent extracted sorbents and Tedlar 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. SUMMARY

[0004] 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.

[0005] 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 0.015 to 1 cc per inhaled breath, or about 0.2 to 12 cc/min for an average 12 breath cycles per minute, can enter the sample collection device during a sampling process.

[0006] 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.

[0007] Sampling for an hour using 15 cm H20 pressure during each pressurization cycle can enable the system to collect between 18 to 720 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 18 and 720 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.

[0008] 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 5mm opening and a depth of l5mm to the start of the adsorbent bed, such as the tubes described in US EPA Method 325. 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figs. 1A-1B illustrate exemplary pressurization patterns for ventilators according to some embodiments of the disclosure.

[0010] Figs. 2A-2B illustrate a sample collection system according to some

embodiments of the disclosure.

[0011] Figs. 3A-3B illustrate coupling that connects the sample collection device to the ventilator outlet line according to some embodiments of the disclosure. [0012] Figs. 4A-4B illustrate the sample collection system coupled to the ventilator outlet line according to some embodiments of the disclosure.

[0013] Figs. 5A-5C illustrate the flow of air in the sample collection system during a sampling process according to some embodiments of the disclosure.

[0014] Figs. 6A-6C illustrate airflow of another sample collection system during sampling according to some embodiments of the disclosure.

[0015] Figs. 7A-7B illustrate another sample collection system according to some embodiments of the disclosure.

[0016] Figs. 8A-8B illustrate another sample collection system according to some embodiments of the disclosure.

[0017] Fig. 9 illustrates a process for collecting a sample according to some

embodiments of the disclosure.

[0018] Fig. 10 illustrates a system block diagram according to some embodiments of the disclosure.

DETAILED DESCRIPTION

[0019] 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. [0020] In some embodiments, sample is collected for a monitoring period of 30 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 15 cm H20 (15 mBar), or about 1.5% of atmospheric pressure, a 3-8cc combined internal volume constitutes about 0.045 - 0.12 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 30-60 minutes, a total volume of 5-500cc 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 100%. A low-wattage (e.g., 2-3 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.

[0021] Figs. 1A-1B 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:

(Volume of Tube, Sleeve, and Reservoir) x (Average cycles per minute) x (sampling period in minutes) x (Pl-P2)/Pa

Where Pl 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 Figs. 2A-6C.

[0022] Fig. 1A illustrates an exemplary pressurization pattern 100 for a ventilator operating in a control mode. In the control mode, breaths are generally initiated by the ventilator. The pressurization pattern 100 illustrates the pressure 102 of the ventilator lines over time 104. As shown in Fig. 1A, during inspiration 110, the pressure 102 in the ventilator lines rises. After inspiration 110 is complete, the pressure 102 in the ventilator lines is allowed to decrease. Inspiration 110 corresponds with a controlled inhale. After inhalation, the patient exhales as the ventilator pressure is reduced.

[0023] Fig. 1B illustrates an exemplary pressurization pattern 120 for a ventilator operating in an assist mode. In the assist mode, breaths are generally initiated by the patient.

The pressurization pattern 120 illustrates the pressure 122 of the ventilator lines over time 124. As shown in Fig. 1B, during inspiration 130, the pressure 122 in the ventilator lines rises. After inspiration 130 is complete, the pressure 122 in the ventilator lines is allowed to decrease.

Inspiration 130 corresponds with a controlled inhale. After inhalation, the patient exhales as the ventilator pressure is reduced.

[0024] Figs. 2A-2B illustrate a sample collection system 201 according to some embodiments of the disclosure. The sample collection system 201 can include a sample collection device 200, a sleeve 250, and caps 270 and 290.

[0025] The sample collection device can include a sampling inlet 202. The inlet 202 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, ¼” TD tubes with a 5mm opening can sample diffusively at up to 0.7cc/min, so active sampling at only l-3cc/min as obtained with ¼” TD tubes would include a diffusive component when using standard thermal desorption tube inlet diameters of about 5 mm. 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 0.031 inches and the outer diameter of the cavity 206 of the sample collection device 200 is in the range of 1/8” to 3/8” and the inner diameter of the cavity 206 of the sample collection device 200 can be less than the outer diameter, such as 0.062” to 0.34” (e.g., 0.195 inches or 5 mm)..

[0026] The sample collection device further includes one or more sorbents 204. The total amount of sorbent used can be in the range of 50-500 mg, with one to three kinds of sorbents 204. When using multiple kinds of sorbents 204 with increasing strength, the sorbents 204 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 204 is around 0.8 to 1.5 inches, with the length of the sample collection device 200 being around 3.5 to 4.5 inches. The bed 204a closest to the inlet 202 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 202 is the“weak” or“weakest” sorbent while the sorbent bed 204c furthest from the inlet 202 is the“strong” or“strongest” sorbent. In some examples, the sample collection device 200 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 5-40 m ² /g of Tenax, Tenax TA, Carbopack C or a similar sorbent, the second sorbent bed 204b includes 30-200 m ² /g of Tenax TA, Carbopack B or a similar sorbent, and the third sorbent bed 204c includes 200-1200 m ² /g of Carbopack X, Carboxen 1000, Carbon Molecular Sieves, or a similar sorbent. Carbopack C, B, X, and Carboxen 1000 are registered trademarks of Supelco (now Sigma Aldrich/Millipore) in

Pennsylvania, United States of America. During analysis, the cavity 206 of the sample collection device 200 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).

[0027] The sample collection device 200 can include a retaining frit 208. The retaining frit 208 retains the sorbent beds 204 in place. It can be advantageous for the sorbents 204 to remain proximate to the opening 202 of the sample collection device 200, thus the retaining frit 208 can be used to retain the sorbents in the position illustrated. By positioning the sorbents 204 away from external seals 210, the sorbents 204 can be heated to a high desorption temperature during desorption while a heat sink (not shown) placed near the external seals 210 can prevent the seals from being damaged due to the high heat. [0028] The sample collection device includes an internal volume 212. Volume 212 is the space in cavity 206 not occupied by the sorbent 204. Volume 212 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 212 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 212 can hold air that has passed through the sorbent 204. Increasing the internal volume of the sample collection system 201 can increase the volume of air that can be sampled during a sampling period of known duration (e.g., an hour).

[0029] The sample collection device further includes a port 214. The port 214 can be located between two of the external seals 2l0a and 2l0b (e.g., the port is between the two lowest of three seals). During sampling, the port 214 allows gas that has passed through the adsorbent to exit the cavity 206 of the sample collection device 200 and flow into the inside 252 of the outer sleeve 250, as will be described in more detail below. During analysis, the port 214 is used to supply a carrier fluid (e.g., a carrier gas) to back desorb the sorbent 204 during GC or GCMS analysis. The seals 210 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 200 further includes an internal seal 216 and valve 218 that seal a top opening 220 during sample collection, transport, and desorption. During sampling, a pressure sensor (not shown) or a balloon (see Figs. 7A-8B) or other elastic, expandable device can be attached to the sample collection device 200 at the valve 218 end to indicate the change in pressure in the sample collection device 200, which indicates that sampling is occurring. In some embodiments, sample collection device 200 does not include internal seal 216, valve 218, and top opening 220 and instead is closed at the top.

[0030] The sleeve 250 can function to isolate the sample collection device 200 when the sample collection device 200 is not in use. The sleeve 250 includes an internal volume 252, threads 254 and threads 256. The sample collection device 200 can be placed into sleeve 200, and cap 290 screws down onto the sleeve 200 at threads 254 to retain the sample collection device 200 within the sleeve 260 until returned to the lab. Cap 290 includes threads 292 that couple to the threads 254 of the sleeve and an opening 294 that allows the top part of the sample collection device 200 to pass through the cap 290 when the cap 290 and sleeve 270 are assembled, as shown in Fig. 2B.

[0031] During sampling, the port 214 of the sample collection device 200 is open to the internal volume 252 of the sleeve 250, as will be described in more detail below. When the sample collection device 200 is not in use, isolation cap 270 can be screwed on to the sleeve 250 at threads 256 to keep the sorbent 204 isolated both before and after sampling. Isolation cap 270 includes threads 272, external seal 274, and internal seal 276. Threads 272 can be coupled to the threads 256 of sleeve 250. External seal 274 forms a seal between the isolation cap 270 and the sleeve 250 when the isolation cap 270 is attached to the sleeve 250. Internal seal 276 provides additional sealing of the inlet 202 of the sample collection device 200.

[0032] Fig. 2B illustrates the sample collection system 201 with the sample collection device 200 fully isolated from its external environment. As shown in Fig. 2B, cap 290 can be screwed onto sleeve 250 at one end of the sample collection device 200 and cap 270 can be screwed onto sleeve 250 at the other end of the sample collection device 200. When assembled in this way, cap 290 is fitted around the sample collection device 200. The sorbent 204 of the sample collection device 200 is sealed from the external environment by the caps 290 and 270 and internal seal 216.

[0033] Figs. 3A-3B illustrate coupling 300 that connects the sample collection device

200 to the ventilator outlet line according to some embodiments of the disclosure. The coupling 300 includes an intake one-way valve 302 and an outlet one-way valve 304 (e.g., check valves). Thus, coupling 300 is a valve system. During sampling, the sample collection device 200 is connected to coupling 300 which connects to the ventilator outlet line at tee 306. The pressure differential rating of the one-way valves 302-304 can be set by the ventilator and/or the patient’s needs or tolerances. The pressure differential of the ventilator cycle can be around 10-15 cm H20 (e.g., 0.14-0.21 psi). The one-way valve 302 can therefore open when the pressure differential from the ventilator outlet line into the sampler is a positive 0.02 to 0.1 psi, while the one-way valve 304 can open when the pressure is greater in the sampler relative to the ventilator outlet line by 0.02-0.1 psi between inspiration pulses. [0034] During inhalation, air from the ventilator output line can flow into the sample collection device 200 through the intake one-way valve 302 of the coupling 300. Intake one way valve 302 can allow selective opening and closing of inlet 312 of the coupling 300. The pressure in the ventilator outlet line, which is higher than the pressure in the sample collection device 200 during inhalation, can cause the intake one-way valve 302 to open. Once inside the sample collection system 201, the air can then flow through the sorbent 204 of the sample collection device 200, allowing the sorbent 204 to adsorb or absorb one or more VOCs present in the exhaled breath.

[0035] During exhalation, the air that has passed through the sorbent 204 can flow through the volume 252 of the sleeve 250 and back into the ventilator output line (e.g., through tee 306) through the outlet one-way valve 304 of the coupling. Outlet one-way valve 304 can allow selective opening and closing of the outlet 314 of the coupling 300. The pressure in the sample collection system 201, which is higher than the pressure in the sample collection device 200 during exhalation, can cause the outlet one-way valve 304 to open. Additional details of the sampling process and the airflow into and out of the sample collection device 200 will be described below.

[0036] Figs. 4A-4B illustrate the sample collection system 201 coupled to the ventilator outlet line according to some embodiments of the disclosure. In some examples, the sample collection device 200 can be received by the hospital in the sleeve and cap assembly illustrated in Fig. 2B. Fig. 4A illustrates the sample collection device without a cap isolating the inlet 202 of the sample collection device 200. Fig. 4A also includes the coupling 300 for fitting the sample collection device to the ventilator outlet line via tee 306. The coupling 300 is sized to fit the inlet end of the sample collection device 200, enabling the sample collection device 200 to collect a sample from the ventilator outlet line once the sample collection device 200 is fitted into the coupling 300. The sample collection device 200 and the coupling 300 can be threadingly coupled.

[0037] Fig. 4B illustrates the sample collection device 200 coupled to the ventilator line by way of coupling 300 and tee 306. When the sample collection device 200 is connected to the coupling 300, sampling can begin. When sampling is done, the process is reversed by unscrewing the sample collection device 200, replacing the isolation cap 270, and then returning the sample collection device 200 in its cap and sleeve assembly to the laboratory for analysis.

[0038] Figs. 5A-5C illustrate the flow of air in the sample collection system 200 during a sampling process according to some embodiments of the disclosure. Fig. 5A illustrates airflow while inspiration (e.g., inhalation) is occurring, and the pressure is increasing by 10 to 20 cm H20 relative to expiration (e.g., exhalation), typically. The gas that is pressurized into the outlet line, and tee 306, is the deep alveolar air left from the end of the previous exhalation. As the pressure increases, the intake one-way valve 302 of coupling 300 allows flow into the inlet 202 of the sample collection device 200 and through the sorbent 204. VOCs are collected by the sorbent 204, and the air, which is not retained by the sorbent 204, continues through the sample collection device 200 where it reaches the port 214. The air continues to flow through the port 214 to the outside of the sample collection device 200 where it is now confined by the volume 252 of the outer sleeve 250. The gas continues to pressurize the rest of the volume down to the outlet one-way valve 304 of the coupling 300. However, while the pressure of the ventilator outlet line is pressurized during inspiration, the one way valve 304 does not allow flow out of the sample collection system 201, as the pressure is greater in the ventilator line than inside the sleeve 250.

[0039] Fig. 5B illustrates airflow through the sample collection system 201 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 200 and its sleeve 250, so no flow can occur through the inlet one-way valve 302. Instead, the gases are drawn out through the back of the sample collection device 200 and into the outer sleeve 250 where it ultimately passes through the outlet one-way valve 304 and back into the ventilator outlet line through tee 306. Thus, air from the ventilator outlet line is drawn into and through the sample collection device 200 and, after sampling has occurred, back into the ventilator outlet line through tee 306 using the pressure cycle of the ventilator outlet line. The sample collection device 200 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 atached to coupling 300 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.

[0040] Fig. 5C illustrates a chart of the change in pressure 506 in the ventilator outlet line and the flow rate 508 of air into the sample collection device 200 during sampling over time 504 as illustrated in Figs. 5A-5B. The pressure 506 in the ventilator outlet line increases during inspiration 510 and decreases during exhalation. During inspiration 510, flow into the sample collection device 200 occurs. Flow into the sample collection device 200 can occur during a period of time that is not as long as the ventilator inspiration stage 510, considering the limited volume of sample collection device 200. For ease of illustration, chart 500 includes indication of flow into the sample collection device 200 (e.g., illustrated in Fig. 5A) but does not include negative flow out of the sample collection device 200 (e.g., illustrated in Fig. 5B).

[0041] Figs. 6A-6C 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 Figs. 2A-5C, with some exceptions noted here. Sample collection system includes a modified coupling 600 that includes a coupling to a reservoir 608. The reservoir has a volume of 1 to 100 cc (e.g., 3 to 10 cc). The coupling 600 to the reservoir 608 includes threads 618 around an opening at which to atach the reservoir 608 and a seal 622 to seal the connection between the coupling 600 and the reservoir 608. Coupling 600 further includes an additional seal 620 to seal the opening of sleeve 250 from the reservoir 608.

[0042] As shown in Fig. 6A, when the inspiration pulse occurs, the reservoir 608 fills with air that enters the sample collection system 201. The reservoir 608 can fill at a higher rate than the cavity 212 of sample collection device 200 because there is no sorbent impeding the flow into the reservoir 606, as there is in the case of flow into the cavity 212 of sample collection device 200 (e.g., sorbent 204).

[0043] As shown in Fig. 6B, after pressurization (e.g., during exhalation), the air can exit the reservoir 508 and flow through the adsorbent 204 and out the outlet one-way valve 304. In some embodiments, a restriction may be used at outlet 314 instead of a one-way valve 304. Since the recovery time is generally 2-4 times longer than the inspiration time, rapid filling of the reservoir 604 must be accomplished, but then flow through the adsorbent 204 may occur over that period where the pressure of the ventilator line is less than that of the reservoir 250 and sample collection device 200 assembly. Having one less valve may improve the long term reliability of the sample collection system 201. In this mode, having the assembly vertical or nearly vertical may allow any return spring in the outlet one-way valve 304 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 300 to seal the ventilator outlet line, or a plunger o-ring combination can automatically close the tee coupling when the sampling device 201 is removed.

[0044] Fig. 6C illustrates a chart of the change in pressure 636 in the ventilator outlet line and the flow rate 638 of air into the sample collection device 200 during sampling over time 634 as illustrated in Figs. 6A-6B. The pressure 636 in the ventilator outlet line increases during inspiration 640 and decreases during exhalation. During inspiration 640, flow into the sample collection device 200 occurs. Flow into the sample collection device 200 can occur during a period of time that does not fully overlap with the ventilator inspiration stage 640 (e.g., flow into the sample collection device 200 can continue to occur after inspiration 640 has ceased). For ease of illustration, chart 630 includes indication of flow into the sample collection device 200 (e.g., illustrated in Fig. 6A) but does not include negative flow out of the sample collection device 200 (e.g., illustrated in Fig. 6B).

[0045] Figs. 7A-7B 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 Figs. 5A-5B and further includes a balloon 700 attached to the sample collection device 200. The balloon 700 is attached with a clip that opens the valve 218 of the sample collection device 200. 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 Figs. 5A-5B). The inclusion of the balloon can also indicate that flow is occurring into and out of the sample collection device 200 as expected during sampling. As shown in Fig. 7A, during inspiration, the balloon 700 is able to inflate slightly due to the increased pressure in the sample collection system. As shown in Fig. 7B, during exhalation, the balloon 700 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 300 to seal the ventilator outlet line.

[0046] Figs. 8A-8B 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 Figs. 6A-6B and further includes a balloon 800 attached to the sample collection device 200. The balloon 800 is attached with a clip that opens the valve 218 of the sample collection device 200. 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 Figs. 6A-6B). The inclusion of the balloon can also indicate that flow is occurring into and out of the sample collection device 200 as expected during sampling. As shown in Fig. 8A, during inspiration, the balloon 800 is able to inflate slightly due to the increased pressure in the sample collection system. As shown in Fig. 8B, during exhalation, the balloon 700 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 300 to seal the ventilator outlet line.

[0047] Fig. 9 illustrates a process for collecting a sample according to some

embodiments of the disclosure. One or more of the systems illustrated in Figs. 2A-6B can be used to perform some or all of the steps of process 900 to collect a sample of target compounds (e.g., VOCs) from exhaled breath in a ventilator outlet line. Process 900 includes a setup process 940, a sampling process 950, and a post-sampling process 960.

[0048] Setup process 940 includes steps 902 and 904. At step 902 of process 900, the valve system (e.g., valve system of coupling 300) is coupled to the ventilator outlet line. As shown in Fig. 3A, the coupling 300 can be attached to a tee 306 that is connected to the ventilator outlet line. Coupling includes an intake one-way valve 302 and an outlet one-way valve 304, as described above. [0049] At step 904 of process 900, the sample collection device 200 is coupled to the valve system (e.g., valve system of coupling 300). Once steps 902 and 904, which can be performed in any order, are complete, the sample collection device 200 is also coupled to the ventilator outlet line through the valve system of the coupling 300.

[0050] 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 Figs. 1A, 1B, 5C, or 6C. 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 200 during steps 906 and 910, described below.

[0051] Sampling process 950 includes steps 906, 908, and 910. In step 906, an inspiration pulse occurs and air flows into the sample collection system 201 through the intake one-way valve 302 of the coupling 300. The flow into the sample collection system 201 is driven by the pressure difference between the ventilator outlet line, which can have an elevated pressure during inspiration, and the sample collection system 200. In some embodiments, such as in embodiments which include a side reservoir 608 that can hold exhaled air, flow into the sample collection system can continue after the inspiration pulse has ceased, as illustrated in Fig. 6C.

[0052] In step 908 of process 900, one or more compounds of interest (e.g., VOCs) present in the exhaled air can be collected in the sorbent 204 of the sample collection device 200. In some embodiments, such as in embodiments that do not include the optional side reservoir 608, collection occurs during the inspiration pulse. In some embodiments, such as in embodiments that include the optional side reservoir 608, collection occurs between inspiration pulses.

[0053] In step 910, which occurs between inspiration pulses of the ventilator inspiration cycle, air flows out of the sample collection device 200 and back into the ventilator outlet line. The air flows through the outlet one-way valve 304 of the coupling. The air that flows out of the sample collection system 200 has already flowed through the sorbent 204 of the sample collection system 200. Thus, air that returns to the ventilator outlet line has already been sampled.

[0054] Post-sampling process 960 includes steps 912 and 914. In step 912, the sample collection device 200 is removed from the coupling 300 or 600. The sample collection device 200 is removed from the coupling 300 or 600 after a sampling period that can last 5 to 60 minutes. After the sample collection device 200 is removed, it can be placed in the cap-and- sleeve assembly including caps 270 and 290 and sleeve 250, such as in Fig. 2B. Isolating the sample collection device 200 in this way prevents the sample from becoming contaminated by the environment external to the sorbent 204 of the sample collection device 200.

[0055] In step 914, a new sample collection device 200 is inserted into the coupling 300 or 600 or a cap or plug is applied to the coupling 300 or 600. A new sample collection device 200 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.

[0056] The flow rate and flow volume through the sample collection device 200 for each breathing cycle depends on the volume between inlet one-way valve 302 and the outlet one-way valve 304. 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 10-15 cm H20. As an example, suppose the pressure change during an exemplary ventilator breath cycle is 12 cm H20, which is about 0.012 atmospheres. As an example, the sample collection device 200 is coupled to a 50cc reservoir 608. Under these exemplary conditions, the volume of sample collected is 0.6cc/breath. With 12 breath cycles per minute under these exemplary conditions, sampling occurs at a rate of 7.2 cc/min, resulting in 2l6cc of air sampled in 30

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 lOcc - lOOcc of air over the course of about 30

minutes. Without the optional reservoir 608, 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 0.7-l5cc/min when using a reservoir 608 with a volume in the range of 5- lOOcc. [0057] Fig. 10 illustrates a system block diagram 800 according to some embodiments of the disclosure. The block diagram 800 includes ventilator pump 1002, ventilator inlet line 1006, the patient 1008, ventilator outlet line 1010, ventilator outlet vent 1012 a valve system 818 including inlet one-way valve 302 and outlet one-way valve 304, the sample collection device 200 including a sorbent 204, and optional reservoir 608. As described above, sorbent 204 can include a plurality of sorbents (e.g., three sorbents) arranged in order of increasing strength. The valve system 818 can be included in coupling 300 or 600.

[0058] Block diagram 1000 illustrates a ventilator system 1014 that includes ventilator pump 1002, ventilator outlet vent 1012 that can open and close, ventilator inlet line 1006, ventilator outlet line 1010, a valve system 818 including inlet one-way valve 302 and outlet one way valve 304, the sample collection device 200 including a sorbent 204, and optional reservoir 608. Additional or alternate components, such as timers, sensors, pressure regulators, and control valves, can be included in the system 1000 without departing from the scope of the disclosure. The block diagram 1000 also illustrates a sample collection system that includes a valve system 818 including inlet one-way valve 302 and outlet one-way valve 304, the sample collection device 200 including a sorbent 204, and optional reservoir 608.

[0059] Ventilator inlet line 1006 can facilitate flow of gas from the ventilator pump 1002 into the patient 1008 (e.g., and into the patient’s lungs to support the patient’s breathing). The patient 1008 is also fluidly coupled to the ventilator outlet line 1010. The ventilator outlet line 1010 can facilitate flow of gas from the patient 1008 to the ventilator outlet vent 1012. Because the ventilator inlet line 1006, ventilator outlet line 1010, and the patientl008 are in fluid communication with one another, when the pressure of the ventilator inlet line 1006 is increased by the ventilator pump 1002, the pressure in the ventilator outlet line 1010 also increases. The periodic increase of pressure in the ventilator outlet line 1010, which is driven by the ventilator pump 1002, drives the flow of gas into the sample collection system 1016, 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 1012, leaving the VOCs trapped on the sampler adsorbent. Ventilator outlet vent 1012 can be a valve or a similar mechanism that opens between inspiration pulses driven by the ventilator pump 1002 and closes during the inspiration pulses. In this way, pressure is allowed to decrease in the ventilator inlet line 1006, the ventilator outlet line 1010, and the patient 1008 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.

[0060] 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.

[0061] 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 9, 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.

[0062] 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.

[0063] Although examples have been fully described with reference to the

accompanying drawings, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of examples of this disclosure as defined by the appended claims.