Gaseous Contrast Agents Research Articles

Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 129Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (1H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner.

Imaging in Asthma Management.

Asthma is a heterogeneous disease characterized by chronic airway inflammation that affects more than 300 million people worldwide. Clinically, asthma has a widely variable presentation and is defined based on a history of respiratory symptoms alongside airflow limitation. Imaging is not needed to confirm a diagnosis of asthma, and thus the use of imaging in asthma has historically been limited to excluding alternative diagnoses. However, significant advances continue to be made in novel imaging methodologies, which have been increasingly used to better understand respiratory impairment in asthma. As a disease primarily impacting the airways, asthma is best understood by imaging methods with the ability to elucidate airway impairment. Techniques such as computed tomography, magnetic resonance imaging with gaseous contrast agents, and positron emission tomography enable assessment of the small airways. Others, such as optical coherence tomography and endobronchial ultrasound enable high-resolution imaging of the large airways accessible to bronchoscopy. These imaging techniques are providing new insights in the pathophysiology and treatments of asthma and are poised to impact the clinical management of asthma.

NMR Spin-Lock Induced Crossing (SLIC) dispersion and long-lived spin states of gaseous propane at low magnetic field (0.05 T)

When parahydrogen reacts with propylene in low magnetic fields (e.g., 0.05T), the reaction product propane develops an overpopulation of pseudo-singlet nuclear spin states. We studied how the Spin-Lock Induced Crossing (SLIC) technique can be used to convert these pseudo-singlet spin states of hyperpolarized gaseous propane into observable magnetization and to detect 1H NMR signal directly at 0.05T. The theoretical simulation and experimental study of the NMR signal dependence on B1 power (SLIC amplitude) exhibits a well-resolved dispersion, which is induced by the spin-spin couplings in the eight-proton spin system of propane. We also measured the exponential decay time constants (TLLSS or TS) of these pseudo-singlet long-lived spin states (LLSS) by varying the time between hyperpolarized propane production and SLIC detection. We have found that, on average, TS is approximately 3 times longer than the corresponding T1 value under the same conditions in the range of pressures studied (up to 7.6atm). Moreover, TS may exceed 13s at pressures above 7atm in the gas phase. These results are in agreement with the previous reports, and they corroborate a great potential of long-lived hyperpolarized propane as an inhalable gaseous contrast agent for lung imaging and as a molecular tracer to study porous media using low-field NMR and MRI.

Aerosols and gaseous contrast agents for magnetic resonance imaging of the lung

Magnetic resonance imaging of lungs and the investigation of pulmonary pathologies with this technique are limited by low proton spin density, degraded magnetic homogeneity and motion. Inhaled contrast agents (gases or aerosols) can improve the diagnostic value of MRI for lung. Paramagnetic contrast agents such as gadolinium chelates aerosol or dioxygen gas increase the relaxivity of proton in lung parenchyma and can be used to assess the ventilated fraction of the bronchoalveolar space. Similarly, inhalation of non proton-MRI nuclei such as perfluorinated gas or hyperpolarized gases ((3)He or (129)Xe) can provide functional ventilation image. In this review paper, the principles, the practical implementation, the limitations and possible safety issues of these different techniques are summarized. The main pre-clinical and clinical applications of these approaches based on oral contrast agents are reviewed and illustrated with cutting-edge lung MRI studies.

Dynamic Oxygen-Enhanced Magnetic Resonance Imaging is Not Useful in Assessing Severity or Airway Inflammation in Asthmatic Children

RATIONALE: Ultrafast dynamic magnetic resonance (MR) imaging has been widely used to evaluate lung function in respiratory disorders, including asthma in adults. Until recently, MR imaging was performed using gaseous contrast agents such as xenon-129 and helium-3. This study investigates whether MR imaging using 100% oxygen may be useful in assessing childhood asthma.

Ultrasound, contrast agents and biological cells; A simplified model for their interaction during in vitro experiments

A model based on simplifying assumptions is described for the time course of an in vitro experiment in which a beam of ultrasound passes through a suspension of biological cells and gaseous contrast agents (UCAs). It is assumed that cavitation-related activation events (AEs) occur, during each of which a UCA is destroyed or becomes nonfunctional and, at the same time, nearby cells are lysed or otherwise altered. If the UCAs are highly concentrated, the ultrasound attenuation is high and may significantly affect the action. The number of cells affected by each AE depends on the concentrations of cells and UCAs as well as the concentration ratio. (E-mail: Wesley.Nyborg@uvm.edu)

Diffusion-weighted 19F-MRI of lung periphery: Influence of pressure and air–SF6 composition on apparent diffusion coefficients

Lung functional magnetic resonance imaging (MRI) has become a reality using different inert hyperpolarized gases, such as 3He and 129Xe, which have provided an extraordinary boost in lung imaging and has also attracted interest to other chemically inert gaseous contrast agents. In this context, we have recently demonstrated the first diffusion-weighted images using thermally polarized inhaled sulfur hexafluoride (SF6) in small animals. The aim of this study was to evaluate whether or not the diffusion coefficient of this fluorinated gas is sensitive to pulmonary structure, gas concentration and air pressure in the airways. Diffusion coefficients of SF6 (both pure and in air mixtures) measured in vitro at different pressures and 20 degrees C showed an excellent agreement with theoretical values. Measurements of diffusion coefficients were also performed in vivo and post-mortem on healthy rats, achieving satisfactory signal-to-noise ratios (SNRs), and SF6 gas was found to be in an almost completely restricted diffusion regime in the lung, i.e., the transport by molecular diffusion is delayed by collisions with barriers such as the alveolar septa. This observed low diffusivity means that this gas will be less sensitive to structural changes in the lungs than other magnetic resonance sensitive gas such as 3He, particularly at human scale. However, it is still possible that SF6 plays a role since it opens a new structural window. Thus, the interest of researchers in delimiting the important limiting technical factors that makes this process very challenging is obvious. Among them, T2 relaxation is very fast, so gradient systems with very fast switching rate and probably large radiofrequency (RF) power and high field systems will be needed for hexafluoride to be used in human studies.

Funktionelle Bildgebung der Lunge mit gasförmigem Kontrastmittel: ³Helium-Magnetresonanztomographie

Current imaging methods of the lung concentrate on morphology as well as on the depiction of the pulmonary parenchyma. The need of an advanced and more subtle imaging technology compared to conventional radiography is met by computed topography as the method of choice. Nevertheless, computed tomography yields very limited functional information. This is to be derived from arterial blood gas analysis, spirometry and body plethysmography. These methods, however, lack the scope for regional allocation of any pathology. Magnetic resonance imaging of the lung has been advanced by the use of hyperpolarised (3)Helium as an inhaled gaseous contrast agent. The inhalation of the gas provides functional data by distribution, diffusion and relaxation of its hyperpolarised state. Because anatomical landmarks of the lung can be visualised as well, functional information can be linked with regional information. Furthermore, the method provides high spatial and temporal resolution and lacks the potential side-effects of ionising radiation. Four different modalities have been established: 1. Spin density imaging studies the distribution of gas, normally after a single inhalation of contrast gas in inspiratory breath hold. 2. Dynamic cine imaging studies the distribution of gas with respect to regional time constants of pulmonary gas inflow. 3. Diffusion weighted imaging can exhibit the presence and severity of pulmonary airspace enlargement, as in pulmonary emphysema. 4. Oxygen sensitive imaging displays intrapulmonary oxygen partial pressure and its distribution. Currently, the method is limited by comparably high costs and limited availability. As there have been recent developments which might bring this modality closer to clinical use, this review article will comprise the methodology as well as the current state of the art and standard of knowledge of magnetic resonance imaging of the lung using hyperpolarised (3)Helium.

Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: Assessment of response to methacholine and exercise challenge

Background: Imaging of gas distribution in the lungs of patients with asthma has been restricted because of the lack of a suitable gaseous contrast agent. Hyperpolarized helium-3 (HHe3) provides a new technique for magnetic resonance imaging of lung diseases. Objective: We sought to investigate the use of HHe3 gas to image the lungs of patients with moderate or severe asthma and to assess changes in gas distribution after methacholine and exercise challenge. Methods: Magnetic resonance imaging was performed in asthmatic patients immediately after inhalation of HHe3 gas. In addition, images were obtained before and after methacholine challenge and a standard exercise test. Results: Areas of the lung with no signal or sharply reduced HHe3 signal (ventilation defects) are common in patients with asthma, and the number of defects was inversely related to the percent predicted FEV1 (r = 0.71, P < .002). After methacholine challenge (n = 3), the number of defects increased. Similarly, imaging of the lungs after exercise (n = 6) showed increased ventilation defects in parallel with decreases in FEV1. The increase in defects after challenge in these 9 asthmatic patients was significant both for the number (P < .02) and extent (P < .02) of the defects. The variability and speed of changes in ventilation and the complete lack of signal in many areas is in keeping with a model in which the defects result from airway closure. Conclusion: HHe3 magnetic resonance provides a new technique for imaging the distribution of inhaled air in the lungs. The technique is suitable for following responses to treatment of asthma and changes after methacholine or exercise challenge. (J Allergy Clin Immunol 2003;111:1205-11.)

Lauriston S. Taylor Lecture: Assuring the safety of medical diagnostic ultrasound.

In 1980, the NCRP formed Scientific Committee 66 with an assignment to address the subject of "biological effects of ultrasound and exposure criteria." It was recognized that the primary source of exposure to ultrasound was through medical applications and, especially, through procedures employing diagnostic ultrasound. While the risk to patients from these procedures was believed small, it was considered important for users to understand it, in view of the widespread use of diagnostic ultrasound. In proceeding with this assignment, much emphasis has been given to the mechanisms by which ultrasound can bring about changes in biological structures or processes. Thermal effects are possible; the local temperature can rise especially rapidly where ultrasound impinges on bone. From theory for heat production and transport, and by analysis of experimental results with mammals, information has been obtained for guiding users in avoiding harm from temperature elevation. Nonthermal effects, such as capillary rupture, can occur when ultrasound is incident on tissue that normally contains gas-filled cavities, as in adult lung or intestine, or on any tissue containing gaseous contrast agents. Theory from fluid dynamics, together with experimental findings, has led to quantitative guidance for avoiding damage from acoustically activated cavities. It is felt that good practice in applying diagnostic ultrasound is best assured by making it possible for users to be well informed on safety matters so that they can feel justifiably confident in making appropriate choices of operating conditions. A promising and useful approach is in the display of safety information on the diagnostic ultrasound screen, which is now a feature of United States standards.

Acoustic detection of microbubble destruction in gaseous contrast agents

The destruction of microbubbles from ultrasound contrast agents has recently received much attention because the disintegration can be used to create new imaging modalities and may produce adverse bioeffects as well. Both passive and active acoustic detection techniques were employed in our experiments to investigate the collective and individual behaviors of contrast microbubbles at different insonification levels. With the passive technique, the oscillation and destruction of microbubbles were studied by characterizing the waveforms of scattered acoustic signals and analyzing the harmonic and noise contents in the spectra of the signals. It was observed that discrete subharmonics and superharmonics (up to the 20th order) were generated at low acoustic pressures. When the bubble destruction occurred at high acoustic pressures, the noise level in the spectra was raised and the discrete harmonic structure in the higher frequency domain reduced to broadband noise. The noise spectrum in the higher frequency range was found to broaden as the acoustic pressure increased. A modified ACD (acoustic cavitation detector) with improved spatial resolution was utilized to study the disintegration process of an individual microbubble. The comparison of results from passive and active detections will be presented.

Subharmonic imaging with gas-filled microbubbles

The nonlinear properties of gaseous contrast agents can be used to create new ultrasound imaging methods, such as harmonic and subharmonic imaging. Those methods are capable of separating the echoes from the contrast bubbles in blood and those from surrounding tissue. Harmonic images are produced by transmitting sound pulses at one frequency, but receiving echoes at double that frequency, while subharmonic images receive echoes at half that frequency. Experiments revealed that the subharmonic component of echoes from some contrast agents, at relatively high acoustic pressure, was greater than the second-harmonic component. Since harmonic imaging suffers from a reduction in image contrast, due to second-harmonic generation during ultrasound propagation, as well as second-harmonic leakage from the transmitted signal, this finding makes subharmonic imaging an attractive alternative to harmonic imaging. Harmonic response measurements with a pulse–echo arrangement and subharmonic images obtained with a modified scanner will be presented. The acoustic pressure threshold for subharmonic generation was found to be quite different for contrast agents with different compositions. The optimal transmitted ultrasound pulses and the reception strategy for subharmonic imaging will also be discussed.

Ultrasonic contrast agents and harmonic imaging

Significant progress has been made in recent years in the development of effective ultrasonic contrast agents for inducing better image contrast of certain anatomic structures in the body for diagnostic purposes. An ideal ultrasonic contrast agent should have the following characteristics: (1) be nontoxic, (2) be capable of producing sufficient contrast via intravenous injection, and (3) have a long persistence time. Gaseous contrast agents such as Albunex■ (Molecular Biosystems), Echovist■ and Levovist■ (Schering), and EchoGen■ (Sonus) have been shown to satisfy a majority of these requirements. Albunex■ was approved in 1994 by the FDA for clinical use. The most intriguing application of these contrast agents is in harmonic pulse-echo and Doppler imaging since nonlinear resonance of microairbubbles would yield echoes at the harmonics of the incident frequency. If detection is made at one of these harmonics, ideally only the signals produced by the bubbles will be seen, allowing a means to discriminate against echoes produced by surrounding tissue structures. In this paper the physical and ultrasonic properties of these agents will be reviewed along with principles of harmonic imaging. Clinical applications of these agents including harmonic imaging and Doppler flow measurements will be discussed. [Work supported by NIH Grant No. HL28452.]

Ein modifiziertes Ultraschall-Dopplerverfahren zum selektiven Nachweis von gashaltigen Kontrastmitteln in vitro und in vivo

The technique presented utilizes the non-linear properties of the oscillating gas bubbles in streaming liquids for diagnostic purposes. The harmonic components of the acoustic waves backscattered from gas bubbles and frequency shifted due to the Doppler effect are evaluated. The technique allows to detect gaseous contrast agents in the blood stream separated from signals of other scatterers like blood cells. Different gaseous contrast agents were studied in vitro in a model circulation system, and the modified Doppler technique was compared with other methods. First in vivo experiments were performed with contrast agents in the cardiovascular system of rabbits.