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.

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.

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.

Computed cardiopulmonography and the idealized lung clearance index, iLCI2.5, in early-stage cystic fibrosis.

This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early-stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early-stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified through CCP parameter σlnCl, was significantly greater (P < 0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (P < 0.002). Participant-specific parameters were used with the CCP model to calculate idealized values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardized. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r = 0.46, P < 0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F ratio = 2.2, P = 0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflects an amalgam of different underlying lung changes in early-stage CF that would require a multiparameter approach, such as potentially CCP, to resolve.NEW & NOTEWORTHY Computed cardiopulmonography is a new technique comprising a highly accurate sensor for measuring respiratory gas exchange coupled with a cardiopulmonary model that is used to identify a set of patient-specific characteristics of the lung. Here, we show that this technique can improve on a standard clinical approach for lung function testing in cystic fibrosis. Most particularly, an approach incorporating multiple model parameters can potentially separate different aspects of pathological change in this disease.

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.

Altered lung physiology in two cohorts after COVID-19 infection as assessed by computed cardiopulmonography.

The longer-term effects of COVID-19 on lung physiology remain poorly understood. Here, a new technique, computed cardiopulmonography (CCP), was used to study two COVID-19 cohorts (MCOVID and C-MORE-LP) at both ∼6 and ∼12 mo after infection. CCP is comprised of two components. The first is collection of highly precise, highly time-resolved measurements of gas exchange with a purpose-built molecular flow sensor based around laser absorption spectroscopy. The second component is estimation of physiological parameters by fitting a cardiopulmonary model to the data set. The measurement protocol involved 7 min of breathing air followed by 5 min of breathing pure O2. One hundred seventy-eight participants were studied, with 97 returning for a repeat assessment. One hundred twenty-six arterial blood gas samples were drawn from MCOVID participants. For participants who had required intensive care and/or invasive mechanical ventilation, there was a significant increase in anatomical dead space of ∼30 mL and a significant increase in alveolar-to-arterial Po2 gradient of ∼0.9 kPa relative to control participants. Those who had been hospitalized had reductions in functional residual capacity of ∼15%. Irrespectively of COVID-19 severity, participants who had had COVID-19 demonstrated a modest increase in ventilation inhomogeneity, broadly equivalent to that associated with 15 yr of aging. This study illustrates the capability of CCP to study aspects of lung function not so easily addressed through standard clinical lung function tests. However, without measurements before infection, it is not possible to conclude whether the findings relate to the effects of COVID-19 or whether they constitute risk factors for more serious disease.NEW & NOTEWORTHY This study used a novel technique, computed cardiopulmonography, to study the lungs of patients who have had COVID-19. Depending on severity of infection, there were increases in anatomical dead space, reductions in absolute lung volumes, and increases in ventilation inhomogeneity broadly equivalent to those associated with 15 yr of aging. However, without measurements taken before infection, it is unclear whether the changes result from COVID-19 infection or are risk factors for more severe disease.

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.

Pulmonary Effects of Sustained Periods of High-G Acceleration Relevant to Suborbital Spaceflight.

AbstractBACKGROUND: Members of the public will soon be taking commercial suborbital spaceflights with significant Gx (chest-to-back) acceleration potentially reaching up to 6 Gx. Pulmonary physiology is gravity-dependent and is likely to be affected, which may have clinical implications for medically susceptible individuals.METHODS: During 2-min centrifuge exposures ranging up to 6 Gx, 11 healthy subjects were studied using advanced respiratory techniques. These sustained exposures were intended to allow characterization of the underlying pulmonary response and did not replicate actual suborbital G profiles. Regional distribution of ventilation in the lungs was determined using electrical impedance tomography. Neural respiratory drive (from diaphragm electromyography) and work of breathing (from transdiaphragmatic pressures) were obtained via nasoesophageal catheters. Arterial blood gases were measured in a subset of subjects. Measurements were conducted while breathing air and breathing 15 oxygen to simulate anticipated cabin pressurization conditions.RESULTS: Acceleration caused hypoxemia that worsened with increasing magnitude and duration of Gx. Minimum arterial oxygen saturation at 6 Gx was 86 1 breathing air and 79 1 breathing 15 oxygen. With increasing Gx the alveolar-arterial (A-a) oxygen gradient widened progressively and the relative distribution of ventilation reversed from posterior to anterior lung regions with substantial gas-trapping anteriorly. Severe breathlessness accompanied large progressive increases in work of breathing and neural respiratory drive.DISCUSSION: Sustained high-G acceleration at magnitudes relevant to suborbital flight profoundly affects respiratory physiology. These effects may become clinically important in the most medically susceptible passengers, in whom the potential role of centrifuge-based preflight evaluation requires further investigation.Pollock RD, Jolley CJ, Abid N, Couper JH, Estrada-Petrocelli L, Hodkinson PD, Leonhardt S, Mago-Elliott S, Menden T, Rafferty G, Richmond G, Robbins PA, Ritchie GAD, Segal MJ, Stevenson AT, Tank HD, Smith TG. Pulmonary effects of sustained periods of high-G acceleration relevant to suborbital spaceflight. Aerosp Med Hum Perform. 2021; 92(7):633641.

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.

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.