The alcohol breath test in practice: effects of exhaled volume.

Alcohol breath test (ABT) measurements are sensitive to the volume of the exhaled breath. Although a minimum breath volume is required for a legally acceptable sample, any additional increase in the volume of exhaled air increases the measurement of breath alcohol concentration (BrAC). Using a sample of 115 ABTs collected by police agencies for evidentiary purposes, we studied the influence of exhaled air volume on the measurement of BrAC. The 115 ABTs were performed on 30 different Alcotest 9510s. Each of the tests included paired, time series measurements of exhaled breath flow rates and breath alcohol content. The exhalation flow rates and exhalation times were used to create exhalation volume-BrAC plots. On average, exhaled air volumes were ~50% of the subjects' age-, height-, race-, and sex-predicted vital capacities (VC). More than 80% of the samples had exhaled air volumes ranging between 30 and 70% of the subject's predicted VC. Breath volumes for duplicate breath samples were similar. For all breath samples, BrAC increased with exhalation volume, an expected behavior for any very high blood solubility compound such as alcohol. Beyond the legally accepted minimum expiratory volume, BrAC increased, on average, at a rate of 9.2 ± 2.8%/liter air exhaled. As a result, a person who exhales just beyond the minimum volume will have a lower BrAC compared with a person who exhales a full VC. Exhaled volume materially impacts the measurement of an ABT. NEW & NOTEWORTHY Subjects who provide breath samples for evidentiary alcohol breath tests exhale, on average, about half of their predicted vital capacity. Because breath alcohol concentration increases with greater exhaled air volume, subjects who exhale more than average volume will have a greater breath alcohol concentration, whereas subjects who exhale less than average volume will have a lesser breath alcohol concentration. A quantification of air volume impact on breath alcohol concentration is provided.

Alcohol breath test: gas exchange issues.

The alcohol breath test is reviewed with a focus on gas exchange factors affecting its accuracy. The basis of the alcohol breath test is the assumption that alveolar air reaches the mouth during exhalation with no change in alcohol concentration. Recent investigations have shown that alcohol concentration is altered during its transit to the mouth. The exhaled alcohol concentration is modified by interaction with the mucosa of the pulmonary airways. Exhaled alcohol concentration is not an accurate indicator of alveolar alcohol concentration. Measuring alcohol concentration in the breath is very different process than measuring a blood level from air equilibrated with a blood sample. Airway exchange of alcohol leads to a bias against certain individuals depending on the anatomic and physiologic characteristics. Methodological modifications are proposed to improve the accuracy of the alcohol breath test to become fair to all.

Airway exchange of highly soluble gases.

Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol.

Airway gas exchange and exhaled biomarkers.

During inspiration and expiration, gases traverse the conducting airways as they are transported between the environment and the alveolar region of the lungs. The term "conducting" airways is used broadly as the airway tree is thought largely to provide a conduit for the respiratory gases, oxygen and carbon dioxide. However, despite a significantly smaller surface area, and thicker barrier separating the gas phase from the blood when compared to the alveolar region, the airway tree can participate in gas exchange under special conditions such as high water solubility, high chemical reactivity, or production of the gas within the airway wall tissue. While these conditions do not apply to the respiratory gases, other gases demonstrate substantial exchange of the airways and are of particular importance to the inflammatory response of the lungs, the medical-legal field, occupational health, metabolic disorders, or protection of the delicate alveolar membrane. Given the significant structural differences between the airways and the alveolar region, the physical determinants that control airway gas exchange are unique and require different models (both experimental and mathematical) to explore. Our improved physiological understanding of airway gas exchange combined with improved analytical methods to detect trace compounds in the exhaled breath provides future opportunities to develop new exhaled biomarkers that are characteristic of pulmonary and systemic conditions.

A multiscale bidirectional coupling framework.

The lung is geometrically articulated across multiple scales from the trachea to the alveoli. A major computational challenge is to tightly link ODEs that describe lower scales to 3D finite element or finite volume models of airway mechanics using iterative communication between scales. In this study, we developed a novel multiscale computational framework for bidirectionally coupling 3D CFD models and systems of lower order ODEs. To validate the coupling framework, a four and eight generation Weibel lung model was constructed. For the coupled CFD-ODE simulations, the lung models were truncated at different generations and a RL circuit represented the truncated portion. The flow characteristics from the coupled models were compared to untruncated full 3D CFD models at peak inhalation and peak exhalation. Results showed that at no time or simulation was the difference in mass flux and/or pressure at a given location between uncoupled and coupled models was greater than 2.43%. The flow characteristics at prime locations for the coupled models showed good agreement to uncoupled models. Remarkably, due to reuse of the Krylov subspace, the cost of the ODE coupling is not much greater than uncoupled full 3D-CFD computations with simple prescribed pressure values at the outlets.

Impact of airway gas exchange on the multiple inert gas elimination technique: theory.

The multiple inert gas elimination technique (MIGET) provides a method for estimating alveolar gas exchange efficiency. Six soluble inert gases are infused into a peripheral vein. Measurements of these gases in breath, arterial blood, and venous blood are interpreted using a mathematical model of alveolar gas exchange (MIGET model) that neglects airway gas exchange. A mathematical model describing airway and alveolar gas exchange predicts that two of these gases, ether and acetone, exchange primarily within the airways. To determine the effect of airway gas exchange on the MIGET, we selected two additional gases, toluene and m-dichlorobenzene, that have the same blood solubility as ether and acetone and minimize airway gas exchange via their low water solubility. The airway-alveolar gas exchange model simulated the exchange of toluene, m-dichlorobenzene, and the six MIGET gases under multiple conditions of alveolar ventilation-to-perfusion, VA/Q, heterogeneity. We increased the importance of airway gas exchange by changing bronchial blood flow, Qbr. From these simulations, we calculated the excretion and retention of the eight inert gases and divided the results into two groups: (1) the standard MIGET gases which included acetone and ether and (2) the modified MIGET gases which included toluene and m-dichlorobenzene. The MIGET mathematical model predicted distributions of ventilation and perfusion for each grouping of gases and multiple perturbations of VA/Q and Qbr. Using the modified MIGET gases, MIGET predicted a smaller dead space fraction, greater mean VA, greater log(SDVA), and more closely matched the imposed VA distribution than that using the standard MIGET gases. Perfusion distributions were relatively unaffected.

Paradigm shift for the alcohol breath test.

The alcohol breath test (ABT) has been used for quantification of ethyl alcohol in individuals suspected of driving under the influence for more than 50 years. In this time, there has been little change in the concepts underlying this single breath test. The old model, which assumes that end-exhaled breath alcohol concentration is closely related to alveolar air alcohol concentration, is no longer acceptable. This paper reviews experimental research and mathematical modeling which has evaluated the pulmonary exchange processes for ethyl alcohol. Studies have shown that alcohol exchanges dynamically with the airway tissue both during inspiration and expiration. The airway tissue interaction makes it impossible to deliver air with alveolar alcohol concentration to the mouth. It is concluded that the ABT is dependent on physiological factors that need to be assessed for accurate testing.

Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine.

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 +/- 0.7 kg, means +/- SD) underwent incremental treadmill exercise tests in normoxia (Fi(O(2)) = 0.21) and hypoxia (Fi(O(2)) = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined Vo(2max). At steady state (~4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over approximately 30 s. Later the fluorescent intensity of each color in each 2-cm(3) lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 +/- 4.2, 4.0 +/- 4.4, and 59.4 +/- 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 +/- 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.

Pulmonary response to 3 h of hypoxia in prone pigs.

Studies in whole animals, isolated lungs and pulmonary tissue strips have shown that the pulmonary vascular resistance (PVR) to hypoxia is temporally biphasic in nature. We studied the regional temporal response to hypoxia in prone pigs. The animals were ventilated with an FIO2 of 0.21 (control), followed by an FIO2 of 0.12 for 180 min. A biphasic response in P(pa) to hypoxia was seen with the first peak between 10 and 20 min and a second rise in P(pa) starting after 30 min, which was due to an increase in cardiac output. Regional blood flow (Q ) and ventilation (V (A)) were measured using i.v. infusion of 15 microm and inhalation of 1 microm fluorescent microspheres, respectively. We grouped the lung pieces according to their temporal relative flow response to hypoxia. The five groups were each spatially distributed similarly, but not identically, among the animals. The corresponding relative ventilation to each group did not vary much. We conclude that in the prone pig, the PVR response to sustained hypoxia varies among regions of the lungs. Following an initial rise in PVR in most lung pieces, we found unexpectedly that some regions continue to increase PVR progressively and while other regions decrease PVR after the initial increase. The net effect is little change of overall PVR to hypoxia with time. Normoxic control animals had little change in their hemodynamics and the large majority of the lung pieces did not change their resistance over 3h. We speculate that the differential response of regions may be due to a differential role of nitric oxide, endothelin-1 release or K(+) channels.

Breath tests and airway gas exchange.

Measuring soluble gas in the exhaled breath is a non-invasive technique used to estimate levels of respiratory, solvent, and metabolic gases. The interpretation of these measurements is based on the assumption that the measured gases exchange in the alveoli. While the respiratory gases have a low blood-solubility and exchange in the alveoli, high blood-soluble gases exchange in the airways. The effect of airway gas exchange on the interpretation of these exhaled breath measurements can be significant. We describe airway gas exchange in relation to exhaled measurements of soluble gases that exchange in the alveoli. The mechanisms of airway gas exchange are reviewed and criteria for determining if a gas exchanges in the airways are provided. The effects of diffusion, perfusion, temperature and breathing maneuver on airway gas exchange and on measurement of exhaled soluble gas are discussed. A method for estimating the impact of airway gas exchange on exhaled breath measurements is presented. We recommend that investigators should carefully control the inspired air conditions and type of exhalation maneuver used in a breath test. Additionally, care should be taken when interpreting breath tests from subjects with pulmonary disease.

Microsphere maps of regional blood flow and regional ventilation.

Systematically mapped samples cut from lungs previously labeled with intravascular and aerosol microspheres can be used to create high-resolution maps of regional perfusion and regional ventilation. With multiple radioactive or fluorescent microsphere labels available, this methodology can compare regional flow responses to different interventions without partial volume effects or registration errors that complicate interpretation of in vivo imaging measurements. Microsphere blood flow maps examined at different levels of spatial resolution have revealed that regional flow heterogeneity increases progressively down to an acinar level of scale. This pattern of scale-dependent heterogeneity is characteristic of a fractal distribution network, and it suggests that the anatomic configuration of the pulmonary vascular tree is the primary determinant of high-resolution regional flow heterogeneity. At approximately 2-cm(3) resolution, the large-scale gravitational gradients of blood flow per unit weight of alveolar tissue account for <5% of the overall flow heterogeneity. Furthermore, regional blood flow per gram of alveolar tissue remains relatively constant with different body positions, gravitational stresses, and exercise. Regional alveolar ventilation is accurately represented by the deposition of inhaled 1.0-microm fluorescent microsphere aerosols, at least down to the approximately 2-cm(3) level of scale. Analysis of these ventilation maps has revealed the same scale-dependent property of regional alveolar ventilation heterogeneity, with a strong correlation between ventilation and blood flow maintained at all levels of scale. The ventilation-perfusion (VA/Q) distributions obtained from microsphere flow maps of normal animals agree with simultaneously acquired multiple inert-gas elimination technique VA/Q distributions, but they underestimate gas-exchange impairment in diffuse lung injury.

Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism.

We studied the roles of endothelins in determining ventilation (Va) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (approximately 23 kg) received autologous clots (approximately 20 g) via a central venous catheter at time = 0 min. The distribution of Va and Q at five different time points (-30, -5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets (group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets (group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean Va/Q was increased, as was Va/Q heterogeneity (log SD Va/Q), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial PO2 or Va/Q mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high Va/Q regions.

The impact of breathing pattern and lung size on the alcohol breath test.

Highly soluble gases exchange primarily with the bronchial circulation through pulmonary airway tissue. Because of this airway exchange, the assumption that end-exhaled alcohol concentration (EEAC) is equal to alveolar alcohol concentration (AAC) cannot be true. During exhalation, breath alcohol concentration (BrAC) decreases due to uptake of ethanol by the airway tissue. It is therefore impossible to deliver alveolar gas to the mouth during a single exhalation without losing alcohol to the airway mucosa. A consequence of airway alcohol exchange is that EEAC is always less than AAC. In this study, we use a mathematical model of the human lung to determine the influence of subject lung size on the relative reduction of BrAC from AAC. We find that failure to inspire a full inspiration reduces the BrAC at full exhalation, but increases the BrAC at minimum exhalation. In addition, a reduced inhaled volume and can lead to an inability to provide an adequate breath volume. We conclude that alcohol exchange with the airways during the single-exhalation breath test is dependent on lung size of the subject with a bias against subjects with smaller lung size.

Therapeutic hypercapnia and ventilation-perfusion matching in acute lung injury: low minute ventilation vs inspired CO2.

STUDY OBJECTIVES: Hypercapnic acidosis has antiinflammatory effects in animal models of acute lung injury (ALI) and improves ventilation-perfusion (V/Q) matching in normal lungs. The effect of hypercapnia on V/Q matching in ALI is conflicting. Hypercapnic acidosis produced by reduced tidal volumes (Vts) was associated with an increased shunt fraction (QS/QT) in patients with ALI compared with control subjects. Vt differences between groups make the assessment of hypercapnic acidosis on V/Q matching difficult. Adding CO2 to the inhaled gas allows the comparison of gas exchange under identical Vt conditions. We hypothesized the presence of hypercapnic acidosis from inspired carbon dioxide (ICD) would improve gas exchange in ALI and would be superior to that of low minute ventilation (LVe) produced by reduced respiratory rate, rather than Vt. DESIGN: University laboratory study of anesthetized New Zealand White rabbits. INTERVENTIONS: Assessment of V/Q relationships using the multiple inert gas elimination technique was performed in 10 saline solution-lavaged animals, which were ventilated with 6 mL/kg Vts and a positive end-expiratory pressure of 8 cm H2O. Each rabbit was studied while it was in eucapnia, followed by hypercapnia (Pa(CO2), 95 to 100 mm Hg) induced by LVe from decreased respiratory rate and by 10% ICD, in random order. MEASUREMENTS AND RESULTS: The Pa(O2) was greater in ICD and LVe compared to eucapnia, but no significant differences in alveolar-arterial oxygen pressure difference or Pa(O2)/fraction of inspired oxygen ratio occurred. LVe statistically reduced the mean V/Q distributions compared with ICD and eucapnia. Log SDs of ventilation and combined retention and excretion curves of the dispersion index were both increased during LVe, indicating the presence of unfavorable changes in ventilation distribution. Neither LVe nor ICD altered the QS/QT. CONCLUSIONS: LVe slightly impairs overall gas exchange and ventilation distribution, but does not increase QS/QT compared with eucapnia and ICD. While ICD does not significantly improve gas exchange, it may be superior to LVe in achieving the antiinflammatory effects of "therapeutic" hypercapnia, since it does not adversely alter gas exchange and has the potential to make the lung more uniformly acidotic.

Ventilation and perfusion distribution during altered PEEP in the left lung in the left lateral decubitus posture with unchanged tidal volume in dogs.

Previous studies in anesthetized humans positioned in the left lateral decubitus (LLD) posture have shown that unilateral positive end-expiratory pressure (PEEP) to the dependent lung produce a more even ventilation distribution and improves gas exchange. Unilateral PEEP to the dependent lung may offer special advantages during LLD surgery by reducing the alveolar-to-arterial oxygen pressure difference {(A-a)PO2 or venous admixture} in patients with thoracic trauma or unilateral lung injury. We measured the effects of unilateral PEEP on regional distribution of blood flow (Q) and ventilation (V(A)) using fluorescent microspheres in pentobarbital anesthetized and air ventilation dogs in left lateral decubitus posture with synchronous lung inflation. Tidal volume to left and right lung is maintained constant to permit the effect on gas exchange to be examined. The addition of unilateral PEEP to the left lung increased its FRC with no change in left-right blood flow distribution or venous admixture. The overall lung V(A)/Q distribution remained relatively constant with increasing unilateral PEEP. Bilateral PEEP disproportionately increased FRC in the right lung but again produced no significant changes in venous admixture or V(A)/Q distribution. We conclude that the reduced dependent lung blood flow observed without PEEP occurs secondary to a reduction in lung volume. When tidal volume is maintained, unilateral PEEP increases dependent lung volume with little effect of perfusion distribution maintaining gas exchange.

Redistribution of blood flow and lung volume between lungs in lateral decubitus postures during unilateral atelectasis and PEEP.

The effect of left lung atelectasis on the regional distribution of blood flow (Q), ventilation (V(A)) and gas exchange on the right lung ventilated with 100% O2 was studied in anesthetized dogs in the lateral decubitus posture. Q and V(A) were measured in 1.7 ml lung volume pieces using injected and aerosolized fluorescent microspheres, respectively. Hypoxic pulmonary vasoconstriction (HPV) in the atelectatic lung shifted flow to the ventilated lung. The increased flow in the ventilated lung ensured adequate gas exchange, compensating for the hypoxemia due to shunt contributed by the atelectatic lung. Left lung atelectasis caused a compensatory increase in the ventilated lung FRC that was smaller in the right (RLD) than left (LLD) lateral posture, the effect of lung compression by the atelectatic lung and mediastinal contents in the RLD posture. The O2 deficit measured by (A-a)DO2 increased with left lung atelectasis and was exacerbated in the LLD posture by 10 cm H2O PEEP, a result of increased shunt caused by a shift in Q from the ventilated to the atelectatic lung. The PEEP-induced O2 deficit was eliminated with inversion to the RLD posture.

The kinetics of transdermal ethanol exchange.

The kinetics of ethanol transport from the blood to the skin surface are incompletely understood. We present a mathematical model to predict the transient exchange of ethanol across the skin while it is being absorbed from the gut and eliminated from the body. The model simulates the behavior of a commercial device that is used to estimate the blood alcohol concentration (BAC). During the elimination phase, the stratum corneum of the skin has a higher ethanol concentration than the blood. We studied the effect of varying the maximum BAC and the absorption rate from the gut on the relationship between BAC and equivalent concentration in the gas phase above the skin. The results showed that the ethanol concentration in the gas compartment always took longer to reach its maximum, had a lower maximum, and had a slower apparent elimination rate than the BAC. These effects increased as the maximum BAC increased. Our model's predictions are consistent with experimental data from the literature. We performed a sensitivity analysis (using Latin hypercube sampling) to identify and rank the importance of parameters. The analysis showed that outputs were sensitive to solubility and diffusivity within the stratum corneum, to stratum corneum thickness, and to the volume of gas in the sampling chamber above the skin. We conclude that ethanol transport through the skin is primarily governed by the washin and washout of ethanol through the stratum corneum. The dynamics can be highly variable from subject to subject because of variability in the physical properties of the stratum corneum.

Measuring airway exchange of endogenous acetone using a single-exhalation breathing maneuver.

Exhaled acetone is measured to estimate exposure or monitor diabetes and congestive heart failure. Interpreting this measurement depends critically on where acetone exchanges in the lung. Health professionals assume exhaled acetone originates from alveolar gas exchange, but experimental data and theoretical predictions suggest that acetone comes predominantly from airway gas exchange. We measured endogenous acetone in the exhaled breath to evaluate acetone exchange in the lung. The acetone concentration in the exhalate of healthy human subjects was measured dynamically with a quadrupole mass spectrometer and was plotted against exhaled volume. Each subject performed a series of breathing maneuvers in which the steady exhaled flow rate was the only variable. Acetone phase III had a positive slope (0.054+/-0.016 liter-1) that was statistically independent of flow rate. Exhaled acetone concentration was normalized by acetone concentration in the alveolar air, as estimated by isothermal rebreathing. Acetone concentration in the rebreathed breath ranged from 0.8 to 2.0 parts per million. Normalized end-exhaled acetone concentration was dependent on flow and was 0.79+/-0.04 and 0.85+/-0.04 for the slow and fast exhalation rates, respectively. A mathematical model of airway and alveolar gas exchange was used to evaluate acetone transport in the lung. By doubling the connective tissue (epithelium+mucosal tissue) thickness, this model predicted accurately (R2=0.94+/-0.05) the experimentally measured expirograms and demonstrated that most acetone exchange occurred in the airways of the lung. Therefore, assays using exhaled acetone measurements need to be reevaluated because they may underestimate blood levels.

Structure and size of bronchopulmonary anastomoses in sheep lung.

The distribution and drainage of bronchial arterial blood flow are complex. We used two different methods to study the bronchial-pulmonary anastomoses in sheep lung. Initially, we injected two different sizes of fluorescent microspheres (15 and 100 microm diameter) into the bronchial artery and histologically determined where the different-size microspheres were entrapped in the lung. In a second series of animals, we injected Microfil into the bronchial artery to observe the anastomotic vessels. The microsphere data confirmed the existence of bronchial-to-pulmonary anastomoses. No microspheres were found in the systemic organs (heart and kidney), confirming the absence of large bronchial artery-to-pulmonary vein anastomoses. Unexpectedly, proportionately more large microspheres (100 microm) lodged in the alveolar parenchyma when compared to 15 microm microspheres. This suggests that there are many more small bronchial (< 100 microm) arterioles feeding the airway mucosa than the larger anastomotic vessels feeding into the parenchyma. In the Microfil cast lungs, we observed four types of anastomotic vessels: bronchial arteries/arterioles that anastomose with pulmonary arteries/arterioles that accompany airways; bronchial arterioles that anastomose directly with parenchymal (and eventually alveolar) vessels; bronchial arterioles that anastomose with blood vessels that do not accompany airways; and bronchial arterioles that anastomose with bronchial veins. Based on our in vivo microsphere data, the vessels that do not accompany the airways are most likely bronchial venules, not pulmonary venules.