What can computed tomography and magnetic resonance imaging tell us about ventilation?

This review provides a summary of pulmonary functional imaging approaches for determining pulmonary ventilation, with a specific focus on multi-detector x-ray computed tomography and magnetic resonance imaging (MRI). We provide the important functional definitions of pulmonary ventilation typically used in medicine and physiology and discuss the fact that some of the imaging literature describes gas distribution abnormalities in pulmonary disease that may or may not be related to the physiological definition or clinical interpretation of ventilation. We also review the current state-of-the-field in terms of the key physiological questions yet unanswered related to ventilation and gas distribution in lung disease. Current and emerging imaging research methods are described, including their strengths and the challenges that remain to translate these methods to more wide-spread research and clinical use. We also examine how computed tomography and MRI might be used in the future to gain more insight into gas distribution and ventilation abnormalities in pulmonary disease.     

Vertical distribution of specific ventilation in normal supine humans measured by oxygen-enhanced proton MRI

Specific ventilation (SV) is the ratio of fresh gas entering a lung region divided by its end-expiratory volume. To quantify the vertical (gravitationally dependent) gradient of SV in eight healthy supine subjects, we implemented a novel proton magnetic resonance imaging (MRI) method. Oxygen is used as a contrast agent, which in solution changes the longitudinal relaxation time (T1) in lung tissue. Thus alterations in the MR signal resulting from the regional rise in O(2) concentration following a sudden change in inspired O(2) reflect SV-lung units with higher SV reach a new equilibrium faster than those with lower SV. We acquired T1-weighted inversion recovery images of a sagittal slice of the supine right lung with a 1.5-T MRI system. Images were voluntarily respiratory gated at functional residual capacity; 20 images were acquired with the subject breathing air and 20 breathing 100% O(2), and this cycle was repeated five times. Expired tidal volume was measured simultaneously. The SV maps presented an average spatial fractal dimension of 1.13 ± 0.03. There was a vertical gradient in SV of 0.029 ± 0.012 cm(-1), with SV being highest in the dependent lung. Dividing the lung vertically into thirds showed a statistically significant difference in SV, with SV of 0.42 ± 0.14 (mean ± SD), 0.29 ± 0.10, and 0.24 ± 0.08 in the dependent, intermediate, and nondependent regions, respectively (all differences, P < 0.05). This vertical gradient in SV is consistent with the known gravitationally induced deformation of the lung resulting in greater lung expansion in the dependent lung with inspiration. This SV imaging technique can be used to quantify regional SV in the lung with proton MRI.     

Physiological evaluation of a new quantitative SPECT method measuring regional ventilation and perfusion.

We have developed a new quantitative single-photon-emission computed tomography (SPECT) method that uses (113m)In-labeled albumin macroaggregates and Technegas ((99m)Tc) to estimate the distributions of regional ventilation and perfusion for the whole lung. The multiple inert-gas elimination technique (MIGET) and whole lung respiratory gas exchange were used as physiological evaluations of the SPECT method. Regional ventilation and perfusion were estimated by SPECT in nine healthy volunteers during awake, spontaneous breathing. Radiotracers were administered with subjects sitting upright, and SPECT images were acquired with subjects supine. Whole lung gas exchange of MIGET gases and arterial Po(2) and Pco(2) gases was predicted from estimates of regional ventilation and perfusion. We found a good agreement between measured and SPECT-predicted exchange of MIGET and respiratory gases. Correlations (r(2)) between SPECT-predicted and measured inert-gas excretions and retentions were 0.99. The method offers a new tool for measuring regional ventilation and perfusion in humans.     

Vertical gradients in regional lung density and perfusion in the supine human lung: the Slinky effect.

In vivo radioactive tracer and microsphere studies have differing conclusions as to the magnitude of the gravitational effect on the distribution of pulmonary blood flow. We hypothesized that some of the apparent vertical perfusion gradient in vivo is due to compression of dependent lung increasing local lung density and therefore perfusion/volume. To test this, six normal subjects underwent functional magnetic resonance imaging with arterial spin labeling during breath holding at functional residual capacity, and perfusion quantified in nonoverlapping 15 mm sagittal slices covering most of the right lung. Lung proton density was measured in the same slices using a short echo 2D-Fast Low-Angle SHot (FLASH) sequence. Mean perfusion was 1.7 +/- 0.6 ml x min(-1) x cm(-3) and was related to vertical height above the dependent lung (slope = -3%/cm, P < 0.0001). Lung density averaged 0.34 +/- 0.08 g/cm3 and was also related to vertical height (slope = -4.9%/cm, P < 0.0001). By contrast, when perfusion was normalized for regional lung density, the slope of the height-perfusion relationship was not significantly different from zero (P = 0.2). This suggests that in vivo variations in regional lung density affect the interpretation of vertical gradients in pulmonary blood flow and is consistent with a simple conceptual model: the lung behaves like a Slinky (Slinky is a registered trademark of Poof-Slinky Incorporated), a deformable spring distorting under its own weight. The greater density of lung tissue in the dependent regions of the lung is analogous to a greater number of coils in the dependent portion of the vertically oriented spring. This implies that measurements of perfusion in vivo will be influenced by density distributions and will differ from excised lungs where density gradients are reduced by processing.     

The Applicability of Amide Proton Transfer Imaging in the Nervous System: Focus on Hypoxic-Ischemic Encephalopathy in the Neonate

In recent years, magnetic resonance imaging (MRI) has become more widely used in neonatal hypoxic-ischemic encephalopathy (HIE), involving, for example, evaluation of cerebral edema, white matter fiber bundle tracking, cerebral perfusion status, and assessment of brain metabolites. MRI has many imaging modalities. However, its application for assessing changes in the internal environment at the tissue and cellular level after hypoxia–ischemia remains a challenge and is currently the focus of intense research. Based on the exchange between amide protons of proteins and polypeptides and free water protons, amide proton transfer (APT) imaging can display changes in pH and protein concentrations in vivo. This paper is a review of the principles of APT imaging, with a focus on the potential application of APT imaging for neonatal HIE.     

Effect of posture on regional gas exchange in pigs.

Although recent high-resolution studies demonstrate the importance of nongravitational determinants for both pulmonary blood flow and ventilation distributions, posture has a clear impact on whole lung gas exchange. Deterioration in arterial oxygenation with repositioning from prone to supine posture is caused by increased heterogeneity in the distribution of ventilation-to-perfusion ratios. This can result from increased heterogeneity in regional blood flow distribution, increased heterogeneity in regional ventilation distribution, decreased correlation between regional blood flow and ventilation, or some combination of the above (Wilson TA and Beck KC, J Appl Physiol 72: 2298-2304, 1992). We hypothesize that, although repositioning from prone to supine has relatively small effects on overall blood flow and ventilation distributions, regional changes are poorly correlated, resulting in regional ventilation-perfusion mismatch and reduction in alveolar oxygen tension. We report ventilation and perfusion distributions in seven anesthetized, mechanically ventilated pigs measured with aerosolized and injected microspheres. Total contributions of pulmonary structure and posture on ventilation and perfusion heterogeneities were quantified by using analysis of variance. Regional gradients of posture-mediated change in ventilation, perfusion, and calculated alveolar oxygen tension were examined in the caudocranial and ventrodorsal directions. We found that pulmonary structure was responsible for 74.0 +/- 4.7% of total ventilation heterogeneity and 63.3 +/- 4.2% of total blood flow heterogeneity. Posture-mediated redistribution was primarily oriented along the caudocranial axis for ventilation and along the ventrodorsal axis for blood flow. These mismatched changes reduced alveolar oxygen tension primarily in the dorsocaudal lung region.     

CT-measured regional specific volume change reflects regional ventilation in supine sheep.

Computer tomography (CT) imaging techniques permit the noninvasive measurement of regional lung function. Regional specific volume change (sVol), determined from the change in lung density over a tidal breath, should correlate with regional ventilation and regional lung expansion measured with other techniques. sVol was validated against xenon (Xe)-CT-specific ventilation (sV) in four anesthetized, intubated, mechanically ventilated sheep. Xe-CT used expiratory gated axial scanning during the washin and washout of 55% Xe. sVol was measured from the tidal changes in tissue density (H, houndsfield units) of lung regions using the relationship sVol = [1,000(Hi - He)]/[He(1,000 + Hi)], where He and Hi are expiratory and inspiratory regional density. Distinct anatomical markings were used to define corresponding lung regions of interest between inspiratory, expiratory, and Xe-CT images, with an average region of interest size of 1.6 +/- 0.7 ml. In addition, sVol was compared with regional volume changes measured directly from the positions of implanted metal markers in an additional animal. A linear relationship between sVol and sV was demonstrated over a wide range of regional sV found in the normal supine lung, with an overall correlation coefficient (R(2)) of 0.66. There was a tight correlation (R(2) = 0.97) between marker-measured volume changes and sVol. Regional sVol, which involves significantly reduced exposure to radiation and Xe gas compared with the Xe-CT method, represents a safe and efficient surrogate for measuring regional ventilation in experimental studies and patients.     

Ventilation distribution in rats: Part I - The effect of gas composition as measured with electrical impedance tomography

ABSTRACT: The measurement of ventilation distribution is currently performed using inhaled tracer gases for multiple breath inhalation studies or imaging techniques to quantify spatial gas distribution. Most tracer gases used for these studies have properties different from that of air. The effect of gas density on regional ventilation distribution has not been studied. This study aimed to measure the effect of gas density on regional ventilation distribution. METHODS: Ventilation distribution was measured in seven rats using electrical impedance tomography (EIT) in supine, prone, left and right lateral positions while being mechanically ventilated with either air, heliox (30% oxygen, 70% helium) or sulfur hexafluoride (20% SF6, 20% oxygen, 60% air). The effect of gas density on regional ventilation distribution was assessed. RESULTS: Gas density did not impact on regional ventilation distribution. The non-dependent lung was better ventilated in all four body positions. Gas density had no further impact on regional filling characteristics. The filling characteristics followed an anatomical pattern with the anterior and left lung showing a greater impedance change during the initial phase of the inspiration. CONCLUSION: It was shown that gas density did not impact on convection dependent ventilation distribution in rats measured with EIT.     

Can we use diffusion MRI as a bio-marker of neurodegenerative processes?

Magnetic resonance imaging (MRI) is an imaging technique with a rapidly expanding application range. This methodology, which relies on quantum physics and substance magnetic properties, is now being routinely used in the clinics and medical research. With the advent of measuring functional brain activity with MRI (functional MRI), this methodology has reached a larger section of the neuroscience community (e.g. psychologists, neurobiologists). In the past, the use of MRI as a biomarker or as an assay to probe tissue pathophysiological condition was limited. However, with the new applications of MRI: molecular imaging, contrast-enhanced imaging and diffusion imaging, MRI is turning into a powerful tool for in vivo characterization of tissue pathophysiology. This review focuses on the diffusion MRI. Although it only measures the averaged Brownian translational motion of water molecules, using different analysis schemes, one can extract a wide range of quantitative indices that represent tissue morphology and compartmentalization. Statistical and visualization routines help to relate these indices to biologically relevant measures such as cell density, water content and size distribution. The aim of this review is to shed light on the potential of this methodology to be used in biological research. To that end, this review is intended for the non-MRI specialists who wish to pursue biological research with this methodology. We will overview the current applications of diffusion MRI and its relation to cellular biology of brain tissue.     

Imaging regional PAO2 and gas exchange

Several methods allow regional gas exchange to be inferred from imaging of regional ventilation and perfusion (V/Q) ratios. Each method measures slightly different aspects of gas exchange and has inherent advantages and drawbacks that are reviewed. Single photon emission computed tomography can provide regional measure of ventilation and perfusion from which regional V/Q ratios can be derived. PET methods using inhaled or intravenously administered nitrogen-13 provide imaging of both regional blood flow, shunt, and ventilation. Electric impedance tomography has recently been refined to allow simultaneous measurements of both regional ventilation and blood flow. MRI methods utilizing hyperpolarized helium-3 or xenon-129 are currently being refined and have been used to estimate local PaO(2) in both humans and animals. Microsphere methods are included in this review as they provide measurements of regional ventilation and perfusion in animals. One of their advantages is their greater spatial resolution than most imaging methods and the ability to use them as gold standards against which new imaging methods can be tested. In general, the reviewed methods differ in characteristics such as spatial resolution, possibility of repeated measurements, radiation exposure, availability, expensiveness, and their current stage of development.     

Visualization of the enzymatic activity in living systems using activated NMR contrast agents

New approaches to the development and some applications of novel paramagnetic "sensing" contrast agents designed for specific visualization of the enzymatic activity in living systems are reviewed. The activation of the above sensing agents includes either the cleavage or the synthesis of reactive precursor compounds that recombine with macromolecules with the formation of immobilized or rotationally inhibited paramagnetic cations. This effect results in strong changes of water proton relaxivity. The need in such agents is justified by efforts to utilize magnetic resonance imaging (MRI) for the visualization of fine structures in the living tissue as well as for increasing the molecular specificity of MRI. The review also contains information regarding recent efforts of increasing the sensitivity of MRI to the presence of paramagnetic cations in living systems.     

Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents.

Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.     

New techniques for the thermal physiologist: using clinical magnetic resonance methods in basic research

Temperature measurement is possible by at least five magnetic resonance imaging (MRI)-methods. All techniques deliver relative units. All techniques have turned out to be useful in dead material. All techniques are sensible to all kinds of movements of or within the body and to measurements in different kinds of tissue. As measuring time is mostly some minutes, application in vivo is still problematic. The main problem for the thermal physiologist is the sensibility of the techniques both to temperature and to perfusion. Great relevance for thermal physiology will turn out with further development of MR-techniques.     

A new nuclear magnetic resonance property of lung

Inflated lung has a nuclear magnetic resonance (NMR) free-induction decay (FID) which is short compared with that of collapsed lung and those of other body tissues. An almost identically short FID is obtained from a slurry of 5-micron alumina particles in water. Interfaces between air and water in lung and between alumina and water in the slurry appear to be the source of spatial internal magnetic inhomogeneities which produce NMR line broadening and the short FID. Paired images that included lung, taken with paired symmetric and asymmetric NMR spin-echo sequences, permit the generation of an image, by subtraction, of the lung isolated from surrounding tissue. These new lung images are neither proton density, T1 (spin-lattice relaxation time), nor T2 (spin-spin relaxation time) images. They complement current NMR images and provide information about regional lung inflation. This previously unrecognized NMR property of lung tissue has potential application in NMR imaging, in quantitative determination of lung water and its distribution, and in the quantitation of regional lung inflation.     

Visualizing lung function with positron emission tomography.

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.     

New concepts in characterization of ischemically injured myocardium by MRI

New concepts regarding the assessment of ischemic myocardial injuries have been addressed in this Minireview using magnetic resonance imaging (MRI). MRI, with its different techniques, brings not only anatomic, but also physiologic, information on ischemic heart disease. It has the ability to measure identical parameters in preclinical and clinical studies. MRI techniques provide the ideal package for repeated and noninvasive assessment of myocardial anatomy, viability, perfusion, and function. MR contrast agents can be applied in a variety of ways to improve MRI sensitivity for detecting and assessing ischemically injured myocardium. With MR contrast agents protocol, it becomes possible to identify ischemic, acutely infarcted, and peri-infarcted myocardium in occlusive and reperfused infarctions. Necrosis specific and nonspecific extracellular contrast-enhanced MRI has been used to assess myocardial viability. Contrast-enhanced perfusion MRI can explore the disturbances in large (angiography) and small coronary arteries (myocardial perfusion) as the underlying cause of myocardial dysfunction. Perfusion MRI has been used to measure myocardial perfusion (ml/min/g) and to demonstrate the difference in transmural myocardial blood flow. Information on no-reflow phenomenon is derived from dynamic changes in regional signal intensity after bolus injection of MR contrast agents. Another development is the near future availability of blood pool MR contrast agents. These agents are able to assess microvascular permeability and integrity and are advantageous in MR angiography (MRA) due to their persistence in the blood. Noncontrast-enhanced MRI such as cine MRI at rest/stress, sodium MRI, and MR spectroscopy also have the potential to noninvasively assess myocardial viability in patients. Futuristic applications for MRI in the heart will focus on identifying coronary artery disease at an early stage and the beneficial effects of new therapeutic agents such as intra-arterial gene therapy. MR techniques will have great future in the drug discovery process and in testing the effects of drugs on myocardial biochemistry, physiology, and morphology. Molecular imaging is going to bloom in this decade.     

Endotoxemia increases relative perfusion to dorsal-caudal lung regions.

Changes in the spatial distribution of perfusion during acute lung injury and their impact on gas exchange are poorly understood. We tested whether endotoxemia caused topographical differences in perfusion and whether these differences caused meaningful changes in regional ventilation-to-perfusion ratios and gas exchange. Regional ventilation and perfusion were measured in anesthetized, mechanically ventilated pigs in the prone position before and during endotoxemia with the use of aerosolized and intravenous fluorescent microspheres. On average, relative perfusion halved in ventral and cranial lung regions, doubled in caudal lung regions, and increased 1.5-fold in dorsal lung regions during endotoxemia. In contrast, there were no topographical differences in perfusion before endotoxemia and no topographical differences in ventilation at any time point. Consequently, endotoxemia increased regional ventilation-to-perfusion ratios in the caudal-to-cranial and dorsal-to-ventral directions, resulting in end-capillary PO2 values that were significantly lower in dorsal-caudal than ventral-cranial regions. We conclude that there are topographical differences in the pulmonary vascular response to endotoxin that may have important consequences for gas exchange in acute lung injury.     

Evaluating bronchodilator effects in chronic obstructive pulmonary disease using diffusion-weighted hyperpolarized helium-3 magnetic resonance imaging

The objective of this study was to evaluate the regional effects of bronchodilator administration in chronic obstructive pulmonary disease (COPD) using hyperpolarized helium-3 ((3)He) MRI apparent diffusion coefficient (ADC). Ten COPD ex-smokers provided written, informed consent and underwent diffusion-weighted, hyperpolarized (3)He MRI, spirometry, and plethysmography before and 25 ± 2 min after bronchodilator administration. Pre- and postsalbutamol whole-lung (WL) ADC maps were generated and registered together to identify the lung regions containing the (3)He signal at both time points, and mean ADC within those regions of interest (ROI) was determined for a measurement of previously ventilated ROI ADC (ADC(P)). Lung ROI with (3)He signal at both time points was used as a binary mask on postsalbutamol WL ADC maps to obtain an ADC measurement for newly ventilated ROI (ADC(N)). Postsalbutamol, no significant differences were detected in WL ADC (P = 0.516). There were no significant differences between ADC(N) and ADC(P) postsalbutamol (P = 1.00), suggesting that the ADC(N) lung regions were not more emphysematous than the lung ROI participating in ventilation before bronchodilator administration. Postsalbutamol, a statistically significant decrease in ADC(P) (P = 0.01) was detected, and there were significant differences between ADC(P) in the most anterior and most posterior image slices (P = 0.02), suggesting a reduction in regional gas trapping following bronchodilator administration. Regional evaluation of tissue microstructure using hyperpolarized (3)He MRI ADC provides insights into lung alterations that accompany improvements in regional (3)He gas distribution after bronchodilator administration.     

Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI

In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.     

A mathematical model of pulmonary gas exchange under inflammatory stress

During a severe local or systemic inflammatory response, immune mediators target lung tissue. This process may lead to acute lung injury and impaired diffusion of gas molecules. Although several mathematical models of gas exchange have been described, none simulate acute lung injury following inflammatory stress. In view of recent laboratory and clinical progress in the understanding of the pathophysiology of acute lung injury, such a mathematical model would be useful. We first derived a partial differential equations model of gas exchange on a small physiological unit of the lung (≈25 alveoli), which we refer to as a respiratory unit (RU). We next developed a simple model of the acute inflammatory response and implemented its effects within a RU, creating a single RU model. Linking multiple RUs with various ventilation/perfusion ratios and taking into account pulmonary venous blood remixing yielded our lung-scale model. Using the lung-scale model, we explored the predicted effects of inflammation on ventilation/perfusion distribution and the resulting pulmonary venous partial pressure oxygen level during systemic inflammatory stresses. This model represents a first step towards the development of anatomically faithful models of gas exchange and ventilation under a broad range of local and systemic inflammatory stimuli resulting in acute lung injury, such as infection and mechanical strain of lung tissue.