Validation of intracardiac shunt using thoracic bioimpedance and inert gas rebreathing in adults before and after percutaneous closure of atrial septal defect in a cardiology research unit: study protocol.

INTRODUCTION: Intrathoracic shunt quantification is a major factor for appropriate clinical management of heart and pulmonary diseases. Intracardiac shunts quantified by pulmonary to systemic output ratio (Qp/Qs) are generally assessed by Doppler echocardiography, MRI or catheterisation. Recently, some authors have suggested the concomitant use of thoracic bioimpedance (TB) and inert gas rebreathing (IGR) techniques for shunt quantification. The purpose of this study is to validate the use of this approach under conditions where shunt fraction is directly quantified such as in patients with isolated atrial septal defect (ASD). METHODS AND ANALYSIS: This trial is a prospective, observational single-centre, non-blinded study of adults seen for percutaneous closure of ASD. Qp/Qs ratio will be directly measured by Doppler echocardiography and direct Fick. IGR and TB will be used simultaneously to measure the cardiac output before and after closure: the ratio of outputs measured by IGR and TB reflecting the shunt fraction. The primary outcome will be the comparison of shunt values measured by TB-IGR and Doppler echocardiography. ETHICS AND DISSEMINATION: The study has been approved by an independent Research Ethics Committee (2017-A03149-44 Fr) and registered as an official clinical trial. The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03437148; Pre-results.

Ventilation/perfusion ratios measured by multiple inert gas elimination during experimental cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) the ventilation/perfusion distribution (VA /Q) within the lung is difficult to assess. This experimental study examines the capability of multiple inert gas elimination (MIGET) to determine VA /Q under CPR conditions in a pig model. METHODS: Twenty-one anaesthetised pigs were randomised to three fractions of inspired oxygen (1.0, 0.7 or 0.21). VA/ Q by micropore membrane inlet mass spectrometry-derived MIGET was determined at baseline and during CPR following induction of ventricular fibrillation. Haemodynamics, blood gases, ventilation distribution by electrical impedance tomography and return of spontaneous circulation were assessed. Intergroup differences were analysed by non-parametric testing. RESULTS: MIGET measurements were feasible in all animals with an excellent correlation of measured and predicted arterial oxygen partial pressure (R(2) = 0.96, n = 21 for baseline; R(2) = 0.82, n = 21 for CPR). CPR induces a significant shift from normal VA /Q ratios to the high VA /Q range. Electrical impedance tomography indicates a dorsal to ventral shift of the ventilation distribution. Diverging pulmonary shunt fractions induced by the three inspired oxygen levels considerably increased during CPR and were traceable by MIGET, while 100% oxygen most negatively influenced the VA /Q. Return of spontaneous circulation were achieved in 52% of the animals. CONCLUSIONS: VA /Q assessment by MIGET is feasible during CPR and provides a novel tool for experimental purposes. Changes in VA /Q caused by different oxygen fractions are traceable during CPR. Beyond pulmonary perfusion deficits, these data imply an influence of the inspired oxygen level on VA /Q. Higher oxygen levels significantly increase shunt fractions and impair the normal VA /Q ratio.

A generic biokinetic model for noble gases with application to radon.

To facilitate the estimation of radiation doses from intake of radionuclides, the International Commission on Radiological Protection (ICRP) publishes dose coefficients (dose per unit intake) based on reference biokinetic and dosimetric models. The ICRP generally has not provided biokinetic models or dose coefficients for intake of noble gases, but plans to provide such information for (222)Rn and other important radioisotopes of noble gases in a forthcoming series of reports on occupational intake of radionuclides (OIR). This paper proposes a generic biokinetic model framework for noble gases and develops parameter values for radon. The framework is tailored to applications in radiation protection and is consistent with a physiologically based biokinetic modelling scheme adopted for the OIR series. Parameter values for a noble gas are based largely on a blood flow model and physical laws governing transfer of a non-reactive and soluble gas between materials. Model predictions for radon are shown to be consistent with results of controlled studies of its biokinetics in human subjects.

The cardiovascular system and diving risk.

Recreational scuba diving is a sport that requires a certain physical capacity, in addition to consideration of the environmental stresses produced by increased pressure, low temperature and inert gas kinetics in tissues of the body. Factors that may influence ability to dive safely include age, physical conditioning, tolerance of cold, ability to compensate for central fluid shifts induced by water immersion, and ability to manage exercise demands when heart disease might compromise exercise capacity. Patients with coronary heart disease, valvular heart disease, congenital heart disease and cardiac arrhythmias are capable of diving, but consideration must be given to the environmental factors that might interact with the cardiac disorder. Understanding of the interaction of the diving environment with various cardiac disorders is essential to providing a safe diving environment to individual divers with known heart disease.

Predictions from a mathematical model of decompression compared to Doppler scores.

This paper describes an attempt to calibrate a mathematical model that predicts the extent of bubble formation in both the tissue and blood of subjects experiencing decompression from a hyperbaric exposure. The model combines an inert gas dynamics model for uptake and elimination of inert anesthetic gases with a simple model of bubble dynamics in perfused tissues. The calibration has been carried out using the model prediction for volume of free gas (bubbles) as microl/ml in central venous blood and relating this to Doppler scores recorded at the end of hyperbaric exposures. More than 1,000 Doppler scores have been compared with the model predictions. Discriminant analysis has been used to determine the cut-points between scores below a certain level and all scores at or above that level. This allows each prediction from the model to be equated to a particular pattern of bubble scores. The predictions from the model are thus given a context against the more familiar Doppler scores as a means of evaluating decompression stress. It is thus possible to use the mathematical model to evaluate decompression stress of a hyperbaric exposure in terms of the predicted volume of gas that will form into bubbles and to convert that to a prediction of the most likely pattern of Doppler grades which would be recorded from a group of subjects experiencing that exposure. This model has been used in assisting regulators to set limits to the level decompression risk that should be considered acceptable and in assisting those working with decompression procedures to design effective modifications.

Inert gas transport in blood and tissues.

This article establishes the basic mathematical models and the principles and assumptions used for inert gas transfer within body tissues-first, for a single compartment model and then for a multicompartment model. From these, and other more complex mathematical models, the transport of inert gases between lungs, blood, and other tissues is derived and compared to known experimental studies in both animals and humans. Some aspects of airway and lung transfer are particularly important to the uptake and elimination of inert gases, and these aspects of gas transport in tissues are briefly described. The most frequently used inert gases are those that are administered in anesthesia, and the specific issues relating to the uptake, transport, and elimination of these gases and vapors are dealt with in some detail showing how their transfer depends on various physical and chemical attributes, particularly their solubilities in blood and different tissues. Absorption characteristics of inert gases from within gas cavities or tissue bubbles are described, and the effects other inhaled gas mixtures have on the composition of these gas cavities are discussed. Very brief consideration is given to the effects of hyper- and hypobaric conditions on inert gas transport.

Simulations of short-time diffusivity in lung airspaces and implications for S/V measurements using hyperpolarized-gas MRI.

We demonstrate a method for simulating restricted diffusion of hyperpolarized gases in lung airspaces that does not rely on an idealized analytic model of alveolar structure. Instead, the restricting geometry was generated from digital representations of histological sections of actual lung tissue obtained from a rabbit model of emphysema. Monte-Carlo simulations of restricted diffusion were performed in the short-time-scale regime, for which the time-dependent diffusivity is quantitatively related to the surface-to-volume ratio (S/V) of the pore space. In each of the eight samples studied, the S/V extracted from the simulated time-dependent diffusivity curves differed by less than 3% from direct assessment of S/V using image-processing methods. Simulated MRI measurements of apparent diffusion coefficients (ADCs) were performed in three representative lung sections to determine the effect of realistic gradient pulse shapes on the extracted S/V values. It was confirmed that ADCs measured at short diffusion times using either narrow or square gradient pulses yield accurate S/V values based on previously derived theoretical relationships. Simulations of triangular and sinusoidal diffusion-sensitizing gradients were then used to quantify the modifications required to extract accurate S/V values from ADC measurements obtained using more realistic gradient waveforms.

Functional lung imaging using hyperpolarized gas MRI.

The noninvasive assessment of lung function using imaging is increasingly of interest for the study of lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Hyperpolarized gas MRI (HP MRI) has demonstrated the ability to detect changes in ventilation, perfusion, and lung microstructure that appear to be associated with both normal lung development and disease progression. The physical characteristics of HP gases and their application to MRI are presented with an emphasis on current applications. Clinical investigations using HP MRI to study asthma, COPD, cystic fibrosis, pediatric chronic lung disease, and lung transplant are reviewed. Recent advances in polarization, pulse sequence development for imaging with Xe-129, and prototype low magnetic field systems dedicated to lung imaging are highlighted as areas of future development for this rapidly evolving technology.

Relationship between two different functions derived from diffusion-based decompression theory.

Hempleman's diffusion-based decompression theory yields two different functions; one is expressed by a simple root function and the other by a complex series function. Although both functions predict the same rate of gas uptake for relatively short exposure times, no clear mathematical explanation has been published that describes the relationship between the two functions. We clarified that (1) the root function is the solution of the one-dimensional diffusion equation for a semi-infinite slab, (2) the series function is an applicable solution for a finite slab thickness, (3) the parameter values of the root function can be used to determine the parameter values of the series function, and (4) the predictions of gas kinetics from both functions agree until an adequate amount of diffusing inert gas reaches the boundary at the opposite end of the finite slab. The last point allows the use of the simpler root function for predicting short no-stop decompression limits. Experience dictates that the inert gas accumulation for a 22 min at 100 feet of seawater (fsw) dive is considered safe for no-stop decompression. Although the constraint, Depth square root of Bottom Time = 100 square root of 22, has been applied as an index to determine either the safe depth or bottom time (given the other) for no-stop decompression, it should not be applied more broadly to dives requiring decompression stops.

Development of a hyperpolarized 129Xe system on 3T for the rat lungs.

MRI (magnetic resonance imaging) with 129Xe has gained much attention as a diagnostic methodology because of its affinity for lipids and possible polarization. The quantitative estimation of net detectability and stability of hyperpolarized 129Xe in the dissolved phase in vivo is valuable to the development of clinical applications. The goal of this study was to develop a stable hyperpolarized 129Xe experimental 3T system to statistically analyze the dissolved-phase 129Xe signal in the rat lungs. The polarization of 129Xe with buffer gases at the optical pumping cell was measured under adiabatic fast passage against the temperature of an oven and laser absorption at the cell. The gases were insufflated into the lungs of Sprague-Dawley rats (n = 15, 400-550 g) through an endotracheal tube under spontaneous respiration. Frequency-selective spectroscopy was performed for the gas phase and dissolved phase. We analyzed the 129Xe signal in the dissolved phase to measure the chemical shift, T2*, delay and its ratio in a rat lungs on 3T. The polarizer was able to produce polarized gas (1.1+/-0.47%, 120 cm3) hundreds of times with the laser absorption ratio (25%) kept constant at the cell. The optimal buffer gas ratio of 25-50% rendered the maximum signal in the dissolved phase. Two dominant peaks of 211.8+/-0.9 and 201.1+/-0.6 ppm were observed with a delay of 0.4+/-0.9 and 0.9+/-1.0 s from the gas phase spectra. The ratios of their average signal to that of the gas phase were 5.6+/-5.2% and 4.4+/-4.7%, respectively. The T2* of the air space in the lungs was 2.5+/-0.5 ms, which was 3.8 times shorter than that in a syringe. We developed a hyperpolarized 129Xe experimental system using a 3T MRI scanner that yields sufficient volume and polarization and quantitatively analyzed the dissolved-phase 129Xe signal in the rat lungs.

Continuous measurement of cardiac output by inert gas throughflow: comparison with thermodilution.

OBJECTIVE: The throughflow method is a new technique for continuous and minimally invasive measurement of cardiac output by the Fick principle, which uses ventilation of the 2 lungs with unequal inspired gas concentrations by means of a double-lumen endobronchial tube. It exploits steady-state gas exchange and thus permits rapid repetition of measurement. DESIGN: Comparison of paired measurements by the throughflow method using N(2)O exchange with bolus thermodilution. SETTING: Departments of anesthesiology in 2 university teaching hospitals. PARTICIPANTS: Nine patients undergoing cardiac surgery in the precardiopulmonary bypass period. INTERVENTIONS: Patients intubated with a double-lumen endobronchial tube were ventilated with 45% nitrous oxide (N(2)O) to the left lung (zero to the right lung). Arterial blood gas samples were taken to measure alveolar deadspace to allow correction for the alveolar-arterial N(2)O difference and to correct for the presence of unmeasured shunt perfusion. MEASUREMENTS AND MAIN RESULTS: Throughflow measurements correlated with thermodilution (r = 0.719, p < 0.05) with a mean bias of -0.208 L/min (-5.2%). The standard error of the bias was 0.060 L/min, with 95% confidence limits for the bias of -0.088 L/min and -0.328 L/min. The limits of agreement between the 2 methods were +0.960 L/min and -1.376 L/min. CONCLUSIONS: The throughflow method showed good agreement with thermodilution. It permits continuous cardiac output measurement without the need for sampling of mixed venous blood, using techniques of lung isolation, which are readily available in clinical anesthetic practice.

Ventilation-perfusion inequality during normoxic and hypoxic exercise in the emu.

Many avian species exhibit an extraordinary ability to exercise under hypoxic condition compared with mammals, and more efficient pulmonary O(2) transport has been hypothesized to contribute to this avian advantage. We studied six emus (Dromaius novaehollandaie, 4-6 mo old, 25-40 kg) at rest and during treadmill exercise in normoxia and hypoxia (inspired O(2) fraction approximately 0.13). The multiple inert gas elimination technique was used to measure ventilation-perfusion (V/Q) distribution of the lung and calculate cardiac output and parabronchial ventilation. In both normoxia and hypoxia, exercise increased arterial Po(2) and decreased arterial Pco(2), reflecting hyperventilation, whereas pH remained unchanged. The V/Q distribution was unimodal, with a log standard deviation of perfusion distribution = 0.60 +/- 0.06 at rest; this did not change significantly with either exercise or hypoxia. Intrapulmonary shunt was <1% of the cardiac output in all conditions. CO(2) elimination was enhanced by hypoxia and exercise, but O(2) exchange was not affected by exercise in normoxia or hypoxia. The stability of V/Q matching under conditions of hypoxia and exercise may be advantageous for birds flying at altitude.

Modelling inert gas exchange in tissue and mixed-venous blood return to the lungs.

Inert gas exchange in tissue has been almost exclusively modelled by using an ordinary differential equation. The mathematical model that is used to derive this ordinary differential equation assumes that the partial pressure of an inert gas (which is proportional to the content of that gas) is a function only of time. This mathematical model does not allow for spatial variations in inert gas partial pressure. This model is also dependent only on the ratio of blood flow to tissue volume, and so does not take account of the shape of the body compartment or of the density of the capillaries that supply blood to this tissue. The partial pressure of a given inert gas in mixed-venous blood flowing back to the lungs is calculated from this ordinary differential equation. In this study, we write down the partial differential equations that allow for spatial as well as temporal variations in inert gas partial pressure in tissue. We then solve these partial differential equations and compare them to the solution of the ordinary differential equations described above. It is found that the solution of the ordinary differential equation is very different from the solution of the partial differential equation, and so the ordinary differential equation should not be used if an accurate calculation of inert gas transport to tissue is required. Further, the solution of the PDE is dependent on the shape of the body compartment and on the density of the capillaries that supply blood to this tissue. As a result, techniques that are based on the ordinary differential equation to calculate the mixed-venous blood partial pressure may be in error.

Effect of process parameters upon the dopamine and lipid peroxidation activity of selected MIG welding fumes as a marker of potential neurotoxicity.

There is growing concern over the neurotoxic effects of chronic occupational exposure to metal fume produced by welding. Elevated iron and manganese levels in the brain have been linked to an increase in lipid peroxidation, dopamine depletion and predisposition to the development of a Parkinson's type condition in advanced cases. Chemical and toxicological analysis of selected welding fumes, generated by model processes, were used in order to evaluate their potential to release solutes that promote oxidation of dopamine and peroxidation of brain lipids in cell free assays. This study compared the effect of shield gas, electrode type and voltage/currect upon the dopamine and brain lipid peroxidation potential of selected welding fume, obtained from metal inert gas (MIG) welding systems. Overall, fume extracts were found to enhance dopamine oxidation and inhibit lipid peroxidation. Significant differences were also found in the oxidising potential of fume generated under differing process conditions; it may therefore be possible to determine the potential neurotoxicity of fumes using this system.

Development of hyperpolarized noble gas MRI.

Magnetic resonance imaging using the MR signal from hyperpolarized noble gases 129Xe and 3He may become an important new diagnostic technique. Alex Pines (adapting the hyperpolarization technique pioneered by William Happer) presented MR spectroscopy studies using hyperpolarized 129Xe. The current authors recognized that the enormous enhancement in the delectability of 129Xe, promised by hyperpolarization, would solve the daunting SNR problems impeding their attempts to use 129Xe as an in vivo MR probe, especially in order to study the action of general anesthetics. It was hoped that hyperpolarized 129Xe MRI would yield resolutions equivalent to that achievable with conventional 1H2O MRI, and that xenon's solubility in lipids would facilitate investigations of lipid-rich tissues that had as yet been hard to image. The publication of hyperpolarized 129Xe images of excised mouse lungs heralded the emergence of hyperpolarized noble-gas MRI. Using hyperpolarized 3He, researchers have obtained images of the lung gas space of guinea pigs and of humans. Lung gas images from patients with pulmonary disease have recently been reported. 3He is easier to hyperpolarize than 129Xe, and it yields a stronger MR signal, but its extremely low solubility in blood precludes its use for the imaging of tissue. Xenon, however, readily dissolves in blood, and the T1, of dissolved 129Xe is long enough for sufficient polarization to be carried by the circulation to distal tissues. Hyperpolarized 129Xe dissolved-phase tissue spectra from the thorax and head of rodents and humans have been obtained, as have chemical shift 129 Xe images from the head of rats. Lung gas 129Xe images of rodents, and more recently of humans, have been reported. Hyperpolarized 129Xe MRI (HypX-MRI) may elucidate the link between the structure of the lung and its function. The technique may also be useful in identifying ventilation-perfusion mismatch in patients with pulmonary embolism, in staging and tracking the success of therapeutic approaches in patients with chronic obstructive airway diseases, and in identifying candidates for lung transplantation or reduction surgery. The high lipophilicity of xenon may allow MR investigations of the integrity and function of excitable lipid membranes. Eventually, HypX-MRI may permit better imaging of the lipid-rich structures of the brain. Cortical brain function is one perfusion-dependent phenomena that may be explored with hyperpolarized 129Xe MR. This leads to the exciting possibility of conducting hyperpolarized 129Xe functional MRI (HypX-fMRI) studies.

Biomedical imaging using hyperpolarized noble gas MRI: pulse sequence considerations.

Hyperpolarized noble gas MRI is a new technique for imaging of gas spaces and tissues that have been hitherto difficult to image, making it a promising diagnostic tool. The unique properties of hyperpolarized species, particularly the non-renewability of the large non-equilibrium spin polarization, raises questions about the feasibility of hyperpolarized noble gas MRI methods. In this paper, the critical issue of T1 relaxation is discussed and it is shown that a substantial amount of polarization should reach the targets of interest for imaging. We analyse various pulse sequence designs, and point out that total scan times can be decreased so that they are comparable or shorter than tissue T1 values. Pulse sequences can be optimized to effectively utilize the non-renewable hyperpolarization, to enhance the SNR, and to eliminate image artifacts. Hyperpolarized noble gas MRI is concluded to be quite feasible.

Diffusion coefficients and solubility coefficients for gases in biological fluids and tissues: a review.

Based on a review of 166 references for diffusion and solubility coefficients in biological fluids and tissues, we have tabulated experimental values for the gases Ar, CO2, H2, He, N2, Ne, N2O, O2, and SF6. Two major conclusions can be drawn: a) for tissues, there is a scarcity of available data; and b) in general, there are significant differences between values determined by different investigators, the discrepancies being most prominent for diffusion coefficients. For water, we give numeric values of the temperature coefficients and preferred diffusion and solubility coefficients at 25 degrees and 37 degrees C. Further, we describe several methods for estimation of coefficients where experimental data are lacking. For tissues, none of the formulas described give precise predictions for all gases, but rough estimates sufficient for most qualitative work can almost always be found. In particular, the data material indicates that for all tissues other than fatty tissues consisting of mainly triacylglycerols, the solubility coefficients for water may be used as a good approximation. Except for SF6, the error in this approximation probably does not exceed 20%. In contrast, diffusion coefficients for most tissues are from 25 to 50% lower than the respective coefficients in water, generally increasing with the water content of the tissue.

Gas exchange in the airways.

The primary function of the lungs is to exchange the respiratory gases, O2 and CO2, between the atmosphere and the blood. Our overall understanding of the lungs as a gas-exchanging organ has improved considerably over the past four decades. We now know that the dynamics of gas exchange depend on the blood solubility (beta b, ml gas ml blood-1 atm-1) of the gas. While the major focus of research has rightly been on the respiratory gases, the lungs exchange a wide spectrum of gases ranging from very low solubility gases such as SF6 or helium (beta b = 0.01) to water vapor (beta b = 20,000). O2 (beta b = 0.7) and CO2 (beta b = 3.0) exchange primarily in the alveolar region of the lung and their exchange is limited by the rate of ventilation and perfusion. In contrast, highly soluble gases (beta b > 100) are likely to exchange primarily in the airways of the lung. We have used exhaled ethanol (beta b = 1756) profiles for humans, steady-state exchange of six inert gases (0.01 < beta b < 300) in an in situ dog trachea, and a mathematical model to analyze the dynamics of airway gas exchange. We make the following conclusion: (1) ethanol exchanges entirely within the airways, and (2) the magnitude of perfusion- and diffusion-related resistance to airway gas exchange is the same.