The Lognormal Lung: A new approach to quantifying lung inhomogeneity in COPD.

Early diagnosis and disease phenotyping in COPD are currently limited by the use of spirometry, which may remain normal despite significant small-airways disease and which may not fully capture a patient's underlying pathophysiology. In this study we explored the use of a new non-invasive technique that assesses gas-exchange inhomogeneity in patients with COPD of varying disease severity (according to GOLD Stage), compared with age-matched healthy controls. The technique, which combines highly accurate measurement of respiratory gas exchange using a bespoke molecular flow sensor and a mechanistic mathematical model of the lung, provides new indices of lung function: the parameters σCL, σCd, and σVD represent the standard deviations of distributions for alveolar compliance, anatomical deadspace and vascular conductance relative to lung volume, respectively. It also provides parameter estimates for total anatomical deadspace and functional residual capacity (FRC). We demonstrate that these parameters are robust and sensitive, and that they can distinguish between healthy individuals and those with mild-moderate COPD (stage 1-2), as well as distinguish between mild-moderate COPD (stage 1-2) and more severe (stage 3-4) COPD. In particular, σCL, a measure of unevenness in lung inflation/deflation, could represent a more sensitive non-invasive marker of early or mild COPD. In addition, by providing a multi-dimensional assessment of lung physiology, this technique may also give insight into the underlying pathophysiological phenotype for individual patients. These preliminary results warrant further investigation in larger clinical research studies, including interventional trials.

Time-resolved observations of vibrationally excited NO X 2Π (v') formed from collisional quenching of NO A 2Σ+ (v = 0) by NO X 2Π: evidence for the participation of the NO a 4Π state.

Time-resolved observations have been made of the formation of vibrationally excited NO X 2Π (v') following collisional quenching of NO A 2Σ+ (v = 0) by NO X 2Π (v = 0). Two time scales are observed, namely a fast production rate consistent with direct formation from the quenching of the electronically excited NO A state, together with a slow component, the magnitude and rate of formation of which depend upon NO pressure. A reservoir state formed by quenching of NO A 2Σ+ (v = 0) is invoked to explain the observations, and the available evidence points to this state being the first electronically excited state of NO, a 4Π. The rate constant for quenching of the a 4Π state to levels v' = 11-16 by NO is measured as (8.80 ± 1.1) × 10-11 cm3 molecule-1 s-1 at 298 K where the error quoted is two standard deviations, and from measurements of the increased formation of high vibrational levels of NO(X) by the slow process we estimate a lower limit for the fraction of self-quenching collisions of NO A 2Σ+ (v = 0) which lead to NO a 4Π as 19%.

Development of in-airway laser absorption spectroscopy for respiratory based measurements of cardiac output.

Respiratory approaches to determining cardiac output in humans are securely rooted in mass balance and therefore potentially highly accurate. To address existing limitations in the gas analysis, we developed an in-airway analyser based on laser absorption spectroscopy to provide analyses every 10 ms. The technique for estimating cardiac output requires both a relatively soluble and insoluble tracer gas, and we employed acetylene and methane for these, respectively. A multipass cell was used to provide sufficient measurement sensitivity to enable analysis directly within the main gas stream, thus avoiding errors introduced by sidestream gas analysis. To assess performance, measurements of cardiac output were made during both rest and exercise on five successive days in each of six volunteers. The measurements were extremely repeatable (coefficient of variation ~ 7%). This new measurement technology provides a stable foundation against which the algorithm to calculate cardiac output can be further developed.

The correlation between breath acetone and blood betahydroxybutyrate in individuals with type 1 diabetes.

Ketone testing is an important element of the self-management of illness in type 1 diabetes. The aim of the present study was to see if a breath test for acetone could be used to predict quantitatively the levels of the ketone betahydroxybutyrate in the blood of those with type 1 diabetes, and thus be used as an alternative to capillary testing for ketones. Simultaneous capillary ketones and breath acetone were measured in 72 individuals with type 1 diabetes attending a diabetes clinic and on 9 individuals admitted to hospital with diabetic ketoacidosis. Capillary blood measurements ranged from 0.1 mmol l-1 (the lower limit of the ketone monitor) to over 7 mmol l-1, with breath acetone varying between 0.25 and 474 parts per million by volume. The two variables were found to be correlated and allowed modelling to be carried out which separated breath acetone levels into three categories corresponding to normal, elevated and 'at risk' levels of blood ketones. The results on this limited set of participants suggest that a breath acetone test could be a simple, non-invasive substitute for capillary ketone measurement in type 1 diabetes.

Accurate real-time FENO expirograms using complementary optical sensors.

The fraction of exhaled nitric oxide (FENO) is an important biomarker for the diagnosis and management of asthma and other pulmonary diseases associated with airway inflammation. In this study we report on a novel method for accurate, highly time-resolved, real time detection of FENO at the mouth. The experimental arrangement is based on a combination of optical sensors for the determination of the temporal profile of exhaled NO and CO2 concentrations. Breath CO2 and exhalation flow are measured at the mouth using diode laser absorption spectroscopy (at 2 µm) and differential pressure sensing, respectively. NO is determined in a sidestream configuration using a quantum cascade laser based, cavity-enhanced absorption cell (at 5.2 µm) which simultaneously measures sidestream CO2. The at-mouth and sidestream CO2 measurements are used to enable the deconvolution of the sidestream NO measurement back to the at-mouth location. All measurements have a time resolution of 0.1 s, limited by the requirement of a reasonable limit of detection for the NO measurement, which on this timescale is 4.7 ppb (2 σ). Using this methodology, NO expirograms (FENOgrams) were measured and compared for eight healthy volunteers. The FENOgrams appear to differ qualitatively between individuals and the hope is that the dynamic information encoded in these FENOgrams will provide valuable additional insight into the location of the inflammation in the airways and potentially predict a response to therapy. A validation of the measurements at low-time resolution is provided by checking that results from previous studies that used a two-compartment model of NO production can be reproduced using our technology.

Novel measure of lung function for assessing disease activity in asthma.

INTRODUCTION: In asthma, lung function measures are often discordant with clinical features such as disease activity or control. METHODS: We investigated a novel technique that provides a measure (σCL) of unevenness (inhomogeneity) in lung inflation/deflation. In particular, we compared σCL with FEV1% predicted (FEV1%pred) as measures of disease activity in the asthmatic lung. RESULTS: σCL correlated modestly with FEV1%pred. However, σCL is not simply a proxy for FEV1%pred as the effects of salbutamol on the two parameters were unrelated. Importantly, σCL reflected disease control better than FEV1. DISCUSSION: We conclude that σCL shows promise as an objective measure of disease activity in asthma.

Potential for noninvasive assessment of lung inhomogeneity using highly precise, highly time-resolved measurements of gas exchange.

Inhomogeneity in the lung impairs gas exchange and can be an early marker of lung disease. We hypothesized that highly precise measurements of gas exchange contain sufficient information to quantify many aspects of the inhomogeneity noninvasively. Our aim was to explore whether one parameterization of lung inhomogeneity could both fit such data and provide reliable parameter estimates. A mathematical model of gas exchange in an inhomogeneous lung was developed, containing inhomogeneity parameters for compliance, vascular conductance, and dead space, all relative to lung volume. Inputs were respiratory flow, cardiac output, and the inspiratory and pulmonary arterial gas compositions. Outputs were expiratory and pulmonary venous gas compositions. All values were specified every 10 ms. Some parameters were set to physiologically plausible values. To estimate the remaining unknown parameters and inputs, the model was embedded within a nonlinear estimation routine to minimize the deviations between model and data for CO2, O2, and N2 flows during expiration. Three groups, each of six individuals, were studied: young (20-30 yr); old (70-80 yr); and patients with mild to moderate chronic obstructive pulmonary disease (COPD). Each participant undertook a 15-min measurement protocol six times. For all parameters reflecting inhomogeneity, highly significant differences were found between the three participant groups ( P < 0.001, ANOVA). Intraclass correlation coefficients were 0.96, 0.99, and 0.94 for the parameters reflecting inhomogeneity in deadspace, compliance, and vascular conductance, respectively. We conclude that, for the particular participants selected, highly repeatable estimates for parameters reflecting inhomogeneity could be obtained from noninvasive measurements of respiratory gas exchange. NEW & NOTEWORTHY This study describes a new method, based on highly precise measures of gas exchange, that quantifies three distributions that are intrinsic to the lung. These distributions represent three fundamentally different types of inhomogeneity that together give rise to ventilation-perfusion mismatch and result in impaired gas exchange. The measurement technique has potentially broad clinical applicability because it is simple for both patient and operator, it does not involve ionizing radiation, and it is completely noninvasive.

An FTIR emission study of the products of NO A2Σ+ (v = 0, 1) + O2 collisions.

Collisional quenching of NO A2Σ+ (v = 0, 1) by O2 has been studied through the detection of vibrationally excited products by time-resolved Fourier transform infrared emission spectroscopy. Non-reactive quenching of NO A2Σ+ (v = 0) produces a vibrational distribution in NO X2Π which has been quantified for v = 2-22, and is found to be bimodal. The results are consistent with two quenching channels. The first forms the ground X3Σ or low-lying a 1Δg electronic state of O2 with a distribution including high vibrational levels of NO X2Π which is slightly hotter than statistical. Two possibilities are identified for the second channel. The first, with a similar quantum yield to that producing higher vibrational levels, forms a highly electronically excited state, such as O2 c1Σ, with low vibrational levels in NO X2Π which are inverted with a distribution resembling that resulting from a sudden or harpoon mechanism. The second is that ground state oxygen is formed with low vibrational energy partitioned into NO X2Π. In addition, vibrationally excited NO2 is observed, but at intensities which indicate that it is formed in low quantum yield. Quantitatively unobservable processes (defined as those which do not form ground state NO (v ≥ 2)) are found to have a branching ratio of at most 25 ± 5%. The results are compared with those of previous studies and the most consistent interpretation suggests that dissociation of O2 to form ground state O(3P) atoms and ground vibrational state NO X2Π (v = 0) is the main reactive process rather than NO2 formation. Qualitatively similar results are seen for the quenching of NO A2Σ+ (v = 1).

Portable Device for Measuring Breath Acetone Based on Sample Preconcentration and Cavity Enhanced Spectroscopy.

A portable and compact device is demonstrated for measuring acetone in breath samples. The device features a 7 cm long high finesse optical cavity as an optical sensor that is coupled to a miniature adsorption preconcentrator containing 0.5 g of polymer material. Acetone is trapped out of breath and released into the optical cavity where it is probed by a near-infrared diode laser operating at ∼1670 nm. With an optical cavity mirror reflectivity of 99.994%, a limit of detection of 159 ppbv (1σ) is demonstrated on samples from breath bags. Initial results on direct breath sampling are presented with a precision of 100 ppbv. The method is validated with measurements made using an ion-molecule reaction mass spectrometer. Data are presented on elevated breath acetone from two individuals following an overnight fast and exercise, and from a third individual during several days of routine behavior.

In-airway molecular flow sensing: A new technology for continuous, noninvasive monitoring of oxygen consumption in critical care.

There are no satisfactory methods for monitoring oxygen consumption in critical care. To address this, we adapted laser absorption spectroscopy to provide measurements of O2, CO2, and water vapor within the airway every 10 ms. The analyzer is integrated within a novel respiratory flow meter that is an order of magnitude more precise than other flow meters. Such precision, coupled with the accurate alignment of gas concentrations with respiratory flow, makes possible the determination of O2 consumption by direct integration over time of the product of O2 concentration and flow. The precision is illustrated by integrating the balance gas (N2 plus Ar) flow and showing that this exchange was near zero. Measured O2 consumption changed by <5% between air and O2 breathing. Clinical capability was illustrated by recording O2 consumption during an aortic aneurysm repair. This device now makes easy, accurate, and noninvasive measurement of O2 consumption for intubated patients in critical care possible.

The Molecular Bronchoscope: A Tool for Measurement of Spatially Dependent CO2 Concentrations in the Lungs.

Respiratory physicians use bronchoscopy for visual assessment of the lungs' topography and collecting tissue samples for external analysis. We propose a novel bronchoscope tool that would enable spatially dependent measurements of the functioning of the lungs by determining local concentrations of carbon dioxide, which will be produced by healthy parts of the lung at rates that are higher than from portions where gas exchange is impaired. The gas analyzer is based on a compact laser absorption spectrometer making use of fiber optics for delivery and return of low intensity diode laser radiation to and from the measurement chamber at the distal end of a flexible conduit. The appropriate optical wavelength was chosen such that light is selectively absorbed only by gaseous CO2. The optical absorption takes place over a short path (8.8 mm) within a rigid, 12 mm long, perforated probe tip. Wavelength modulation spectroscopy was adopted as the analytical technique to reduce the noise on the optical signal and yield measurements of relative CO2 concentration every 180 ms with a precision as low as 600 part-per-million by volume. The primary objective of such a device is to see if additional spatial information about the lungs functionality can be gathered, which will complement visual observation.

Comparison of breath gases, including acetone, with blood glucose and blood ketones in children and adolescents with type 1 diabetes.

Previous studies have suggested that breath gases may be related to simultaneous blood glucose and blood ketone levels in adults with type 2 and type 1 diabetes. The aims of this study were to investigate these relationships in children and young people with type 1 diabetes in order to assess the efficacy of a simple breath test as a non-invasive means of diabetes management. Gases were collected in breath bags and measurements were compared with capillary blood glucose and ketone levels taken at the same time on a single visit to a routine hospital clinic in 113 subjects (59 male, age 7 years 11 months-18 years 3 months) with type 1 diabetes. The patients were well-controlled with relatively low concentrations of the blood ketone measured (ß hydroxybutyrate, 0-0.4 mmol l(-1)). Breath acetone levels were found to increase with blood ß hydroxybutyrate levels and a significant relationship was found between the two (Spearman's rank correlation ρ = 0.364, p < 10(-4)). A weak positive relationship was found between blood glucose and breath acetone (ρ = 0.16, p = 0.1), but led to the conclusion that single breath measurements of acetone do not provide a good measure of blood glucose levels in this cohort. This result suggests a potential to develop breath gas analysis to provide an alternative to blood testing for ketone measurement, for example to assist with the management of type 1 diabetes.

RF noise induced laser perturbation for improving the performance of non-resonant cavity enhanced absorption spectroscopy.

We present a novel strategy for suppressing mode structure which often degrades off-axis cavity enhanced absorption spectra. This strategy relies on promoting small, random fluctuations in the optical frequency by perturbing the injection current of the diode laser source with radio frequency (RF) bandwidth-limited white noise. A fast and compact oxygen sensor, constructed from a 764 nm vertical-cavity surface-emitting laser (VCSEL) and an optical cavity with re-entrant configuration, is employed to demonstrate the potential of this scheme for improving the sensitivity and robustness of a field-deployable cavity spectrometer. The RF spectral density of the current noise injected into the VCSEL has been measured, and correlated to the effects on the optical spectral signal-to-noise ratio (SNR) and laser linewidth for a range of re-entrant geometries. A fourfold gain in the SNR has been achieved using the RF noise perturbation for the optimal off-axis alignment, which led to a minimum detectable absorption (MDA) predicted from an Allan variance study as low as 4.3 × 10(-5) at 1 s averaging. For the optically forbidden oxygen transition under investigation, a limit of detection (SNR = 1) of 810 ppm was achieved for a 10 ms acquisition time. This performance level paves the way for a fast, sensitive, in-line oxygen spectrometer that lends itself to a range of applications in respiratory medicine.

Laser-based method and sample handling protocol for measuring breath acetone.

A robust method is demonstrated to measure acetone in human breath at sub parts-per-million by volume (ppmv) concentrations using diode laser cavity enhanced absorption spectroscopy. The laser operates in the near-infrared at about 1690 nm probing overtone transitions in acetone in a spectral region relatively free from interference from common breath species such as CO2, water, and methane. Using an optical cavity with a length of 45 cm, bound by mirrors of 99.997% reflectivity, a limit of detection of ∼180 parts-per-billion by volume (ppbv) (1σ) of breath acetone is achieved. The method is validated with measurements made with an ion-molecule reaction mass spectrometer. A technique to calibrate the optical cavity mirror reflectivity using a temperature dependent water vapor source is also described.

Rate constants for collisional quenching of NO (A(2)Σ(+), v = 0) by He, Ne, Ar, Kr, and Xe, and infrared emission accompanying rare gas and impurity quenching.

The quenching rates of NO (A(2)Σ(+), v = 0) with He, Ne, Ar, Kr and Xe have been studied at room temperature by measurements of the time dependence of the fluorescence decay following laser excitation. The rates are slow, with upper limits of rate constants determined as between 1.2 and 2.0 × 10(-14) cm(3) molecule(-1) s(-1), considerably lower than those reported before in the literature. Such slow rates can be markedly influenced by impurities such as O2 and H2O which have quenching rate constants close to gas kinetic values. Time resolved Fourier transform infrared emission has been used to observe the products of the quenching processes with the rare gases and with impurities. For He, Ne Ar and Kr there is no difference within experimental error of the populations in NO (X(2)Π v ≥ 2) produced with and without rare gas present, but the low quantum yields of such quenching (of the order of 5% for an atmosphere of rare gas) preclude quantitative information on the quantum states being obtained. For quenching by Xe the collisional formation of electronically excited Xe atoms dominates the emission at early times. Vibrationally excited NO (X(2)Π, v) and products of reactive quenching are observed in the presence of O2 and H2O.

Demonstration of a novel laser-driven light source for broadband spectroscopy between 170 nm and 2.1 µm.

Combining broadband light sources with optical cavities is a well established approach to sensitive monitoring of trace species in both gas and liquid phases. Here we investigate for the first time the potential of a novel source based on laser-driven xenon plasma technology for spectroscopic studies of gaseous species over the 170-2100 nm spectral range.

Products of the quenching of NO A 2Σ+ (v = 0) by N2O and CO2.

Collisional quenching of NO A (2)Σ(+) (v = 0) by N(2)O and CO(2) has been studied through measurements of vibrationally excited products by time resolved Fourier transform infrared emission. In both cases vibrationally excited NO X (2)Π (v) is seen and quantified in levels v≥ 2 with distributions which are close to statistical. However the quantum yields to produce these levels are markedly different for the two quenchers. For CO(2) such quenching accounts for only ca. 26% of the total: for N(2)O it is ca. 85%. Far more energy is seen in the internal modes of the CO(2) product than those of N(2)O. The results are rationalised in terms of cleavage of the N(2)-O bond being dominant in the latter case, with either a similar O atom production or a specific channel producing almost exclusively NO in low vibrational levels (v = 0,1) for quenching by CO(2). Minor reactive channels yielding NO(2) are seen in both cases, and O((1)D) is observed with low quantum yield in the reaction with N(2)O. The results are discussed in terms of previous models of the quenching processes, and are consistent with the very high yield of NO X (2)Π (v = 0) previously observed by laser induced fluorescence for quenching of NO A (2)Σ(+) (v = 0) by CO(2).

Demonstration of a mid-infrared cavity enhanced absorption spectrometer for breath acetone detection.

A high-resolution absorption spectrum of gaseous acetone near 8.2 µm has been taken using both Fourier transform and quantum cascade laser (QCL)-based infrared spectrometers. Absolute absorption cross sections within the 1215-1222 cm(-1) range have been determined, and the spectral window around 1216.5 cm(-1) (σ = 3.4 × 10(-19) cm(2) molecule(-1)) has been chosen for monitoring trace acetone in exhaled breath. Acetone at sub parts-per-million (ppm) levels has been measured in a breath sample with a precision of 0.17 ppm (1σ) by utilizing a cavity enhanced absorption spectrometer constructed from the QCL source and a linear, low-volume, optical cavity. The use of a water vapor trap ensured the accuracy of the results, which have been corroborated by mass spectrometric measurements.

Noise-immune cavity-enhanced optical heterodyne detection of HO2 in the near-infrared range.

Accurate measurements of the absolute concentrations of radical species present in the atmosphere are invaluable for better understanding atmospheric processes and their impact on Earth systems. One of the most interesting species is HO(2), the hydroperoxyl radical, whose atmospheric daytime levels are on the order of 10 ppt and whose observation therefore requires very sensitive detection techniques. In this work, we demonstrate the first steps toward the application of external-cavity diode-laser-based noise-immune cavity-enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) to the detection of the HO(2) radical in the near-infrared range. Measurements of stable species and of HO(2) were made in a laboratory setting, and the possibilities of extending the sensitivity of the technique to atmospheric conditions are discussed.