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Real-time breath gas analysis of carbon monoxide: laser-based detection and pulmonary gas exchange modeling
Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.ORCID iD: 0000-0002-7272-533X
2018 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Realtidsanalys av kolmonoxid i utandningsluften : detektion med laserspektroskopi och modellering av gasutbytet i lungorna (Swedish)
Abstract [en]

Breath gas analysis is a promising approach for non-invasive medical diagnostics and physiological monitoring. Real-time, breath-cycle resolved biomarker detection facilitates data interpretation and has the potential to improve the diagnostic value of breath tests as exhalation profiles carry spatiotemporal information about biomarker origin and gas exchange in the respiratory tract. This thesis presents and scrutinizes a novel methodology for the analysis of real-time breath data, where single-exhalation profiles are simulated using a pulmonary gas exchange model and least-squares fitted to measured expirograms to extract airway and alveolar contributions and diffusing capacities. The methodology is demonstrated on exhaled breath carbon monoxide (eCO), a candidate biomarker for oxidative stress and respiratory diseases. The thesis mainly covers (1) the construction of a compact optical sensor based on tunable diode laser absorption spectroscopy (TDLAS) in the mid-infrared region (4.7 μm) for selective and precise real-time detection of CO in breath and ambient air (detection limit 9 ± 5 ppb at 0.1 s), (2) the design of an advanced online breath sampling system, (3) the implementation of a trumpet model with axial diffusion (TMAD) to simulate the CO gas exchange, and (4) the application of extended eCO analysis in clinical studies to establish the healthy non-smoker baseline of the eCO parameters and to study the response to CO and wood smoke exposure. It is shown that the TMAD adequately describes the gas exchange during systemic CO elimination for different breathing patterns, and that there is no difference between eCO parameters from mouth- and nose exhalations. Expirogram shape and eCO parameters exhibit a dependence on the exhalation flow rate, but for a given breathing maneuverer, the parameters lie in a narrow range. Airway CO is close to and correlates with ambient air CO, indicating negligible airway production in the healthy population. The alveolar diffusing capacity is independent of endogenous CO, even after exposure to elevated exogenous CO, and could be used to assess lung diffusion abnormalities. Compared to CO exposure, no clear additional effect of exposure to wood smoke particles on eCO is observed. The discrimination between endogenous and exogenous CO sources remains a challenge.

Abstract [sv]

Detektion av spårgaser i utandningsluften har stor potential för icke-invasiv medicinsk diagnostik och fysiologisk övervakning. Realtid andningsgasanalys av enskilda andningscykler underlättar datatolkningen och kan förbättra det diagnostiska värdet av andningstester, eftersom utandningsprofiler bär spatiotemporal information om biomarkörens ursprung och gasutbyte i andningssystemet. Denna avhandling presenterar och granskar en ny analysmetod, där utandningsprofiler simuleras med hjälp av en matematisk modell för gasutbytet, och anpassas till uppmätta expirogram för att bestämma luftvägs- och alveolära bidrag och diffusionsförmågor. Metoden demonstreras på utandad kolmonoxid (eCO), en potentiell biomarkör för oxidativ stress och respiratoriska sjukdomar. Avhandlingen omfattar huvudsakligen (1) konstruktionen av en kompakt optisk sensor baserat på mid-infraröd diodlaserabsorptionsspektroskopi (TDLAS) vid 4.7 μm för selektiv och precis realtidsmätning av CO i utandnings- och omgivningsluften (detektionsgräns 9 ± 5 ppb vid 0.1 s), (2) design av ett avancerat system för online provtagning, (3) adaption av en matematisk lungmodell med axiell diffusion (TMAD) för simulation av CO gasutbytet, och (4) tillämpningen av utökad eCO analys i kliniska studier för att fastställa baslinjen för eCO parametrarna i friska icke-rökare, och för att studera effekten av exponering för CO och trärök. Det visas att modellen väl beskriver gasutbytet under systemiskt CO utsläpp för olika andningsmönster, och att det inte finns någon skillnad mellan eCO parametrarna från utandning via mun och näsa. Utandningsprofilerna och eCO parametrarna ändras beroende på utandningsflödet, men för ett visst andningsmönstret ligger parametrarna i ett smalt område. Koncentrationen av CO i luftvägarna ligger nära och korrelerar med CO i omgivningsluften, vilket indikerar att CO produktionen i luftvägarna är försumbart hos den friska befolkningen. Den alveolär diffusionsförmågan är oberoende av endogen CO, även efter exponering för förhöjd exogen CO, och kan möjligtvis användas för att diagnosticera en nedsatt diffusionsförmåga. Jämfört med exponering för CO observeras ingen tydlig ytterligare effekt av exponering för trärökpartiklar. Att åtskilja endogena och exogena eCO källor förbli en utmaning.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2018. , p. 95
Keywords [en]
carbon monoxide (CO), pulmonary gas exchange, computational modeling, real-time breath gas analysis, single-exhalation profile, laser absorption spectroscopy, nonlinear least-squares fitting, breath sampling, baseline level, diurnal variation, healthy population, exposure study
National Category
Physiology Bioinformatics (Computational Biology) Atom and Molecular Physics and Optics Medical Laboratory and Measurements Technologies
Research subject
Physics; Physiology
Identifiers
URN: urn:nbn:se:umu:diva-152099ISBN: 978-91-7601-930-6 (print)OAI: oai:DiVA.org:umu-152099DiVA, id: diva2:1251325
Public defence
2018-10-19, Lilla hörsalen KBE301, KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-28 Created: 2018-09-26 Last updated: 2018-10-18Bibliographically approved
List of papers
1. Real-time breath gas analysis of CO and CO2 using an EC-QCL
Open this publication in new window or tab >>Real-time breath gas analysis of CO and CO2 using an EC-QCL
2017 (English)In: Applied physics. B, Lasers and optics (Print), ISSN 0946-2171, E-ISSN 1432-0649, Vol. 123, no 5, article id 144Article in journal (Refereed) Published
Abstract [en]

Real-time breath gas analysis is a promising, non-invasive tool in medical diagnostics, and well-suited to investigate the physiology of carbon monoxide (CO), a potential biomarker for oxidative stress and respiratory diseases. A sensor for precise, breath-cycle resolved, simultaneous detection of exhaled CO (eCO) and carbon dioxide (eCO2) was developed based on a continuous wave, external-cavity quantum cascade laser (EC-QCL), a low-volume multi-pass cell and wavelength modulation spectroscopy. The system achieves a noise-equivalent (1σ) sensitivity of 8.5 × 10−8 cm−1 Hz−1/2 and (2σ) detection limits of 9 ± 2 ppbv and 650 ± 7 ppmv at 0.14 s spectrum acquisition time for CO and CO2, respectively. Integration over 15 s yields a precision of 0.6 ppbv for CO. The fact that the eCO2 expirograms measured by capnography and laser spectroscopy have essentially identical shape confirms true real-time detection. It is found that the individual eCO exhalation profiles from healthy non-smokers have a slightly different shape than the eCO2 profiles and exhibit a clear dependence on exhalation flow rate and breath-holding time. Detection of indoor air CO and broadband breath profiling across the 93 cm−1 mode-hop-free tuning range of the EC-QCL are also demonstrated.

Place, publisher, year, edition, pages
Springer, 2017
National Category
Atom and Molecular Physics and Optics Medical Laboratory and Measurements Technologies Physiology
Identifiers
urn:nbn:se:umu:diva-135366 (URN)10.1007/s00340-017-6715-x (DOI)000402982600006 ()
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2018-09-26Bibliographically approved
2. ICL-based TDLAS sensor for real-time breath gas analysis of carbon monoxide isotopes
Open this publication in new window or tab >>ICL-based TDLAS sensor for real-time breath gas analysis of carbon monoxide isotopes
2017 (English)In: Optics Express, ISSN 1094-4087, E-ISSN 1094-4087, Vol. 25, no 11, p. 12743-12752Article in journal (Refereed) Published
Abstract [en]

We present a compact sensor for carbon monoxide (CO) in air and exhaled breath based on a room temperature interband cascade laser (ICL) operating at 4.69 µm, a low-volume circular multipass cell and wavelength modulation absorption spectroscopy. A fringe-limited (1σ) sensitivity of 6.5 × 10−8 cm−1Hz-1/2 and a detection limit of 9 ± 5 ppbv at 0.07 s acquisition time are achieved, which constitutes a 25-fold improvement compared to direct absorption spectroscopy. Integration over 10 s increases the precision to 0.6 ppbv. The setup also allows measuring the stable isotope 13CO in breath. We demonstrate quantification of indoor air CO and real-time detection of CO expirograms from healthy non-smokers and a healthy smoker before and after smoking. Isotope ratio analysis indicates depletion of 13CO in breath compared to natural abundance.

Place, publisher, year, edition, pages
Optical Society of America, 2017
Keywords
Laser sensors, Spectroscopy - infrared, Spectroscopy - laser, Biological sensing and sensors, Semiconductor lasers - quantum cascade
National Category
Medical Laboratory and Measurements Technologies Atom and Molecular Physics and Optics Physical Chemistry Physiology
Identifiers
urn:nbn:se:umu:diva-135377 (URN)10.1364/OE.25.012743 (DOI)000403940700064 ()
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2018-09-26Bibliographically approved
3. Modeling pulmonary gas exchange and single-exhalation profiles of carbon monoxide
Open this publication in new window or tab >>Modeling pulmonary gas exchange and single-exhalation profiles of carbon monoxide
2018 (English)In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 927Article in journal (Refereed) Published
Abstract [en]

Exhaled breath carbon monoxide (eCO) is a candidate biomarker for non-invasive assessment of oxidative stress and respiratory diseases. Standard end-tidal CO analysis, however, cannot distinguish, whether eCO reflects endogenous CO production, lung diffusion properties or exogenous sources, and is unable to resolve a potential airway contribution. Coupling real-time breath gas analysis to pulmonary gas exchange modeling holds promise to improve the diagnostic value of eCO. A trumpet model with axial diffusion (TMAD) is used to simulate the dynamics of CO gas exchange in the respiratory system and corresponding eCO concentrations for the first time. The mass balance equation is numerically solved employing a computationally inexpensive routine implementing the method of lines, which provides the distribution of CO in the respiratory tract during inhalation, breath-holding and exhalation with 1 mm spatial and 0.01 s temporal resolution. Initial estimates of the main TMAD parameters, the maximum CO fluxes and diffusing capacities in alveoli and airways, are obtained using healthy population tissue, blood and anatomical data. To verify the model, mouth-exhaled expirograms from two healthy subjects, measured with a novel, home-built laser-based CO sensor, are compared to single-exhalation profiles simulated using actual breath sampling data, such as exhalation flow rate (EFR) and volume. A very good agreement is obtained in exhalation phases I and III for EFRs between 55 and 220 ml/s and after 10 s and 20 s of breath-holding, yielding a unique set of TMAD parameters. The results confirm the recently observed EFR dependence of CO expirograms and suggest that measured end-tidal eCO is always lower than alveolar and capillary CO. Breath-holding allows the observation of close-to-alveolar CO concentrations and increases the sensitivity to the airway TMAD parameters in exhalation phase I. A parametric simulation study shows that a small increase in airway flux can be distinguished from an increase in alveolar flux, and that slight changes in alveolar flux and diffusing capacity have a significantly different effect on phase III of the eCO profiles.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
carbon monoxide (CO), pulmonary gas exchange, computational modeling, real-time breath gas analysis, single-exhalation profile, laser absorption spectroscopy
National Category
Physiology Bioinformatics (Computational Biology) Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-150270 (URN)10.3389/fphys.2018.00927 (DOI)000440204000001 ()
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-11-01Bibliographically approved
4. Fitting of single-exhalation profiles using a pulmonary gas exchange model: application to carbon monoxide
Open this publication in new window or tab >>Fitting of single-exhalation profiles using a pulmonary gas exchange model: application to carbon monoxide
2019 (English)In: Journal of Breath Research, ISSN 1752-7155, E-ISSN 1752-7163, Vol. 13, no 2, article id 026001Article in journal (Refereed) Published
Abstract [en]

Real-time breath gas analysis coupled to gas exchange modeling is emerging as promising strategy to enhance the information gained from breath tests. It is shown for exhaled breath carbon monoxide (eCO), a potential biomarker for oxidative stress and respiratory diseases, that a weighted, nonlinear least-squares fit of simulated to measured expirograms can be used to extract physiological parameters, such as airway and alveolar concentrations and diffusing capacities. Experimental CO exhalation profiles are acquired with high time-resolution and precision using mid-infrared tunable diode laser absorption spectroscopy and online breath sampling. A trumpet model with axial diffusion is employed to generate eCO profiles based on measured exhalation flow rates and volumes. The concept is demonstrated on two healthy non-smokers exhaling at a flow rate of 250 ml s−1 during normal breathing and at 120 ml s−1 after 10 s of breath-holding. The obtained gas exchange parameters of the two subjects are in a similar range, but clearly distinguishable. Over a series of twenty consecutive expirograms, the intra-individual variation in the alveolar parameters is less than 6%. After a 2 h exposure to 10 ± 2 ppm CO, end-tidal and alveolar CO concentrations are significantly increased (by factors of 2.7 and 4.9 for the two subjects) and the airway CO concentration is slightly higher, while the alveolar diffusing capacity is unchanged compared to before exposure. Using model simulations, it is found that a three-fold increase in maximum airway CO flux and a reduction in alveolar diffusing capacity by 60% lead to clearly distinguishable changes in the exhalation profile shape. This suggests that extended breath CO analysis has clinical relevance in assessing airway inflammation and chronic obstructive pulmonary disease. Moreover, the novel methodology contributes to the standardization of real-time breath gas analysis.

Place, publisher, year, edition, pages
Institute of Physics Publishing (IOPP), 2019
Keywords
real-time breath gas analysis, carbon monoxide (CO), pulmonary gas exchange model, single-exhalation profile, laser absorption spectroscopy
National Category
Physiology Bioinformatics (Computational Biology) Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-152093 (URN)10.1088/1752-7163/aafc91 (DOI)000460174200001 ()30620936 (PubMedID)
Note

Originally included in thesis in manuscript form 

Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2019-03-27Bibliographically approved
5. Extended breath CO analysis: baseline and diurnal variation of pulmonary gas exchange parameters
Open this publication in new window or tab >>Extended breath CO analysis: baseline and diurnal variation of pulmonary gas exchange parameters
(English)Manuscript (preprint) (Other academic)
National Category
Physiology Other Medical Sciences not elsewhere specified Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-152095 (URN)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-27

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