A real-time recording setup combining exhaled breath volatile organic compound (VOC) measurements by proton transfer reaction-mass spectrometry (PTR-MS) with hemodynamic and respiratory data is presented. Continuous automatic sampling of exhaled breath is implemented on the basis of measured respiratory flow: a flow-controlled shutter mechanism guarantees that only end-tidal exhalation segments are drawn into the mass spectrometer for analysis. Exhaled breath concentration profiles of two prototypic compounds, isoprene and acetone, during several exercise regimes were acquired, reaffirming and complementing earlier experimental findings regarding the dynamic response of these compounds reported by Senthilmohan et al (2000 Redox Rep. 5 151-3) and Karl et al (2001 J. Appl. Physiol. 91 762-70). While isoprene tends to react very sensitively to changes in pulmonary ventilation and perfusion due to its lipophilic behavior and low Henry constant, hydrophilic acetone shows a rather stable behavior. Characteristic (median) values for breath isoprene concentration and molar flow, i.e., the amount of isoprene exhaled per minute are 100 ppb and 29 nmol min(-1), respectively, with some intra-individual day-to-day variation. At the onset of exercise breath isoprene concentration increases drastically, usually by a factor of ∼3-4 within about 1 min. Due to a simultaneous increase in ventilation, the associated rise in molar flow is even more pronounced, leading to a ratio between peak molar flow and molar flow at rest of ∼11. Our setup holds great potential in capturing continuous dynamics of non-polar, low-soluble VOCs over a wide measurement range with simultaneous appraisal of decisive physiological factors affecting exhalation kinetics. In particular, data appear to favor the hypothesis that short-term effects visible in breath isoprene levels are mainly caused by changes in pulmonary gas exchange patterns rather than fluctuations in endogenous synthesis.

Human breath contains a myriad of endogenous volatile organic compounds (VOCs) which are reflective of ongoing metabolic or physiological processes. While research into the diagnostic potential and general medical relevance of these trace gases is conducted on a considerable scale, little focus has been given so far to a sound analysis of the quantitative relationships between breath levels and the underlying systemic concentrations. This paper is devoted to a thorough modeling study of the end-tidal breath dynamics associated with isoprene, which serves as a paradigmatic example for the class of low-soluble, blood-borne VOCs. Real-time measurements of exhaled breath under an ergometer challenge reveal characteristic changes of isoprene output in response to variations in ventilation and perfusion. Here, a valid compartmental description of these profiles is developed. By comparison with experimental data it is inferred that the major part of breath isoprene variability during exercise conditions can be attributed to an increased fractional perfusion of potential storage and production sites, leading to higher levels of mixed venous blood concentrations at the onset of physical activity. In this context, various lines of supportive evidence for an extrahepatic tissue source of isoprene are presented. Our model is a first step towards new guidelines for the breath gas analysis of isoprene and is expected to aid further investigations regarding the exhalation, storage, transport and biotransformation processes associated with this important compound.

In this phenomenological study we focus on dynamic measurements of volatile organic compounds (VOCs) in exhaled breath under exercise conditions. An experimental setup efficiently combining breath-by-breath analyses using proton transfer reaction mass spectrometry (PTR-MS) with data reflecting the behaviour of major hemodynamic and respiratory parameters is presented. Furthermore, a methodology for complementing continuous VOC profiles obtained by PTR-MS with simultaneous SPME/GC-MS measurements is outlined. These investigations aim at evaluating the impact of breathing patterns, cardiac output or blood pressure on the observed breath concentration and allow for the detection and identification of several VOCs revealing characteristic rest-to-work transitions in response to variations in ventilation or perfusion. Examples of such compounds include isoprene, methyl acetate, butane, DMS and 2-pentanone. In particular, both isoprene and methyl acetate exhibit a drastic rise in concentration shortly after the onset of exercise, usually by a factor of about 3-5 within approximately 1 min of pedalling. These specific VOCs might also be interpreted as potentially sensitive indicators for fluctuations of blood or respiratory flow and can therefore be viewed as candidate compounds for future assessments of hemodynamics, pulmonary function and gas exchange patterns via observed VOC behaviour.

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide (NO) have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which may reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways, (ii) the concentrations in the tracheo-bronchial lining fluid, (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, the model illuminates the discrepancies between observed and theoretically predicted blood-breath ratios of acetone during resting conditions, i.e., in steady state. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases and thus is expected to have general relevance for a wider range of blood-borne inert gases. The chief intention of the present modeling study is to provide mechanistic relationships for further investigating the exhalation kinetics of acetone and other water-soluble species. This quantitative approach is a first step towards new guidelines for breath gas analyses of volatile organic compounds, similar to those for nitric oxide.

Isothermal rebreathing has been proposed as an experimental technique for estimating the alveolar levels of hydrophilic volatile organic compounds (VOCs) in exhaled breath. Using the prototypic test compounds acetone and methanol, we demonstrate that the end-tidal breath profiles of such substances during isothermal rebreathing show a characteristic increase that contradicts the conventional pulmonary inert gas elimination theory due to Farhi. On the other hand, these profiles can reliably be captured by virtue of a previously developed mathematical model for the general exhalation kinetics of highly soluble, blood-borne VOCs, which explicitly takes into account airway gas exchange as a major determinant of the observable breath output. This model allows for a mechanistic analysis of various rebreathing protocols suggested in the literature. In particular, it predicts that the end-exhaled levels of acetone and methanol measured during free tidal breathing will underestimate the underlying alveolar concentration by a factor of up to 1.5. Moreover, it clarifies the discrepancies between in vitro and in vivo blood-breath ratios of hydrophilic VOCs and yields further quantitative insights into the physiological components of isothermal rebreathing and highly soluble gas exchange in general.

Isoprene is one of the most abundant endogenous volatile organic compounds (VOCs) contained in human breath and is considered to be a potentially useful biomarker for diagnostic and monitoring purposes. However, neither the exact biochemical origin of isoprene nor its physiological role is understood in sufficient depth, thus hindering the validation of breath isoprene tests in clinical routine. Exhaled isoprene concentrations are reported to change under different clinical and physiological conditions, especially in response to enhanced cardiovascular and respiratory activity. Investigating isoprene exhalation kinetics under dynamical exercise helps to gather the relevant experimental information for understanding the gas exchange phenomena associated with this important VOC. The first model for isoprene in exhaled breath has been developed by our research group. In this paper, we aim at giving a concise overview of this model and describe its role in providing supportive evidence for a peripheral (extrahepatic) source of isoprene. In this sense, the results presented here may enable a new perspective on the biochemical processes governing isoprene formation in the human body.

In this paper we develop a simple two compartment model which extends the Farhi equation to the case when the inhaled concentration of a volatile organic compound (VOC) is not zero. The model connects the exhaled breath concentration of systemic VOCs with physiological parameters such as endogenous production rates and metabolic rates. Its validity is tested with data obtained for isoprene and inhaled deuterated isoprene-D5.

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