Pulmonary Disorders: Ventilation-Perfusion MR Imaging with Animal ...

Qun Chen, PhD David L. Levin, MD, PhD Ducksoo Kim, MD Vivek David, MD Michelle McNicholas, MD Victoria Chen Peter M. Jakob, PhD Mark A. Griswold, BSc James W. Goldfarb, MSc Hiroto Hatabu, MD, PhD Robert R. Edelman, MD

Index terms: Bronchi, stenosis or obstruction, 671.90 Embolism, experimental studies, 60.72 Gadolinium Lung, MR, 60.121411, 60.121413, 60.12143 Lung, perfusion Lung, ventilation Oxygen Radiology 1999; 213:871–879 Abbreviations: FLASH ⫽ fast low-angle shot RARE ⫽ rapid acquisition with relaxation enhancement ROI ⫽ region of interest SI ⫽ signal intensity 1 From the Dept of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, AN-241, Boston, MA 02215. From the 1998 RSNA scientific assembly. Received Aug 26, 1998; revision requested Oct 22; revision received Feb 18, 1999; accepted Jul 1. Q.C. supported by Scientist Development Grant from the American Heart Association and Genentech. R.R.E. supported in part by grant R01HL57437 from National Institutes of Health and the Lauterbur Award from the Society of Computed Body Tomography and Magnetic Resonance. M.M. supported in part by 1996 RSNA seed grant. Address reprint requests to Q.C. (e-mail: [email protected] .edu). r RSNA, 1999

Author contributions: Guarantors of integrity of entire study, Q.C., R.R.E.; study concepts, Q.C., D.L.L., D.K., V.D., R.R.E.; study design, Q.C., D.K., M.M.; definition of intellectual content, Q.C., D.L.L., V.D., P.M.J., H.H.; literature research, Q.C.; experimental studies, Q.C., P.M.J., V.C., D.K., M.M., J.W.G.; data acquisition, Q.C., V.C., M.M., D.K.; data analysis, Q.C., V.C., M.A.G., J.W.G.; statistical analysis, Q.C., P.M.J., M.A.G.; manuscript preparation and editing, Q.C., D.L.L.; manuscript review, Q.C., D.L.L., D.K., V.D., M.M., P.M.J., M.A.G., J.W.G., H.H., R.R.E.

Pulmonary Disorders: Ventilation-Perfusion MR Imaging with Animal Models1 PURPOSE: To demonstrate the capability of magnetic resonance (MR) imaging to assess alteration in regional pulmonary ventilation and perfusion with animal models of airway obstruction and pulmonary embolism. MATERIALS AND METHODS: Airway obstruction was created by inflating a 5-F balloon catheter into a secondary bronchus. Pulmonary emboli were created by injecting thrombi into the inferior vena cava. Regional pulmonary ventilation was assessed with 100% oxygen as a T1 contrast agent. Regional pulmonary perfusion was assessed with a two-dimensional fast low-angle shot, or FLASH, sequence with short repetition and echo times after intravenous administration of gadopentetate dimeglumine. RESULTS: Matched ventilation and perfusion abnormalities were identified in all animals with airway obstruction. MR perfusion defects without ventilation abnormalities were seen in all animals with pulmonary emboli. CONCLUSION: Ventilation and perfusion MR imaging are able to provide regional pulmonary functional information with high spatial and temporal resolution. The ability of MR imaging to assess both the magnitude and regional distribution of pulmonary functional impairment could have an important effect on the evaluation of lung disease.

The assessment of regional pulmonary ventilation and perfusion is essential for the evaluation of a variety of lung disorders. Despite continued advances in medical imaging, the techniques used to assess regional pulmonary ventilation and perfusion are limited. The only method that is routinely used in a clinical setting is radionuclide ventilationperfusion scintigraphy. Although this technique is noninvasive and widely available, it is limited by poor spatial and temporal resolution and by the use of radioactive substances. Berthezene et al (1) demonstrated the feasibility of magnetic resonance (MR) ventilation imaging in a rat model with aerosolized gadopentetate dimeglumine as a contrast agent. Combined with gadopentetate dimeglumine–enhanced perfusion imaging, their results showed that MR imaging is able to demonstrate regional pulmonary ventilation and perfusion. However, gadopentetate dimeglumine is not approved by the U.S. Food and Drug Administration in the form of an inhaled aerosol; thus, this approach is not available in clinical settings. Recently, hyperpolarized gases such as helium 3 and xenon 129 have been used for MR ventilation imaging (2,3). Although promising, these methods also have disadvantages. Among these are the high cost of the apparatus for gas polarization and the need for special MR imaging hardware. We recently developed MR imaging techniques to assess pulmonary ventilation and perfusion on a regional basis. In these, oxygen is used as a T1 contrast agent to assess pulmonary ventilation (4,5), and a bolus of gadopentetate dimeglumine is used to assess pulmonary perfusion (6,7). These methods not only obviate radioactive substances but also result in images with better spatial and temporal resolution than are achieved with radionuclide scintigraphy. Moreover, since oxygen is readily available and intravenous gadopentetate dimeglumine is currently in routine use, implementation of these techniques in a clinical setting is a straightforward process. The purpose of this study was to evaluate these methods in the assessment of regional pulmonary ventilation and perfusion with pig models of airway obstruction and pulmonary embolism. 871

MATERIALS AND METHODS All experiments were conducted with a 1.5-T system (Vision Magnetom; Siemens, Erlangen, Germany). The system has a resonant echo-planar imaging capability with minimum gradient rise time of 300 µsec or nonresonant rise time of 600 µsec to peak gradient amplitude of 25 mT/m along three axes. All animal studies were approved by the animal care and use committee at our institution.

MR Imaging Techniques Ventilation imaging.—Regional ventilation was assessed with oxygen as a T1 contrast agent. T1-weighted coronal images were acquired with an inversion-recovery single-shot turbo spin-echo sequence while the animals received mechanical ventilation alternately with either room air or 100% oxygen. Centrically reordered phase encoding was used to produce high signal-to-noise ratio (5). The observed signal intensity (SI) change in the lung results from the shortening of the proton spin-lattice relaxation time (T1) in the lung tissue and blood, owing to the paramagnetic effect of molecular oxygen (4). The spin-echo nature of the sequence minimizes the sensitivity to field inhomogeneities within the lung tissue. The short interecho spacing reduces the duration of the data collection (approximately 538 msec for a 128 ⫻ 256 matrix), making it relatively insensitive to respiratory motion artifacts. Imaging parameters included the following: repetition time msec/echo time (effective) msec of 5,000/4.2, matrix of 128 ⫻ 256, interecho time of 4.2 msec, readout bandwidth of 650 Hz per pixel, section thickness of 8–12 mm, and field of view of 35–40 ⫻ 35–40 cm. To obtain the maximal SI difference between the ventilation of room air and oxygen, the delay time, or inversion time, between the inversion pulse and the beginning of data acquisition was adjusted from 600 to 1,100 msec at a 100-msec interval. One posterior section location was used for this process, which took approximately 5 minutes to complete. The inversion time determined with this process was then used for the rest of the study. Perfusion imaging.—Pulmonary perfusion was assessed with a two-dimensional fast low-angle shot (FLASH) (8) MR sequence with short repetition and echo times after the intravenous administration of a T1-shortening contrast agent, gadopentetate dimeglumine (Magnevist; 872 • Radiology • December 1999

Berlex Laboratories, Wayne, NJ). A short echo time was used to overcome the SI loss owing to the short T2* of lung tissue. Ten milliliters of gadopentetate dimeglumine was administered as a 4-second intravenous bolus. The bolus was synchronized to the start of the two-dimensional dynamic FLASH sequence. Data for five to six coronal sections were acquired at 2.0– 3.5-second intervals for 60–75 seconds. Sequence parameters included the following: 3.0/0.9 with flip angle of 25°, readout bandwidth of 976 Hz per pixel, 8–12-mm section thickness, 128 ⫻ 128 matrix, and field of view of 35–40 ⫻ 35–40 cm. Anatomic imaging.—T2-weighted coronal images were obtained with a standard

a.

half-Fourier rapid acquisition with relaxation enhancement (RARE) sequence (HASTE; Siemens) (3,000 [effective]/43 [effective]). T1-weighted coronal images were acquired with an inversion-recovery single-shot turbo spin-echo sequence (5,000 [effective]/4.2 [effective]/600 [inversion time msec]). Intermediateweighted coronal images were acquired with a centrically reordered single-shot turbo spin-echo sequence (5,000 [effective]/4.2 [effective]). These images were used for comparison with the ventilation and perfusion MR images. Other imaging parameters for all three sequences were section thickness of 8–12 mm, field of view of 35–40 ⫻ 35–40 cm, matrix of

b.

Figure 1. Pig 1. Airway obstruction model. (a) T1-weighted, coronal, inversion-recovery single-shot turbo spin-echo image (5,000 [effective]/4.2 [effective]/600) in a posterior section shows the inflated balloon (arrow). (b) T2-weighted, coronal, standard half-Fourier RARE image (3,000 [effective]/43 [effective]) was obtained at the same section location as in a. No abnormalities were observed in a or b.

a.

b.

Figure 2. Pig 1. (a) Ventilation coronal RARE MR image (5,000/4.2) shows ventilation defect in the lower lobe of the right lung (arrowheads). (b) Perfusion coronal FLASH MR image (3.0/0.9) shows matched perfusion deficit (arrowheads) caused by hypoxic vasoconstriction. Chen et al

128 ⫻ 256, interecho time of 4.2 msec, readout bandwidth of 650 Hz per pixel.

Animal Models Airway occlusion model.—Seven Yorkshire pigs (23–30 kg) were studied. Animals were anesthetized (preanesthesia with ketamine hydrochloride 20 mg per kilogram of body weight, xylazine hydrochloride 2 mg/kg, and atropine sulfate 0.04 mg/kg), intubated, and allowed to breathe either room air or 100% oxygen. An arterial catheter was placed for blood pressure and blood gas monitoring. Airway obstruction was created by placing a 5-F balloon catheter (Medi-tech/Boston Scientific, Watertown, Mass) in a second-

ary bronchus with fluoroscopic guidance. The balloon was inflated with 3% iodinated contrast agent for better visualization during placement of the balloon. The animals were then immediately transported from the animal preparation facility to the MR imaging suite. The experiment with pig 4 was postponed for 11⁄2 hours owing to technical problems with the MR imaging system. This delay led to postobstructive collapse. Data from this animal were presented separately and compared with that from the other six animals. Pulmonary embolism model.—Six Yorkshire pigs (24–27 kg) were studied. Animals were anesthetized (ketamine hydrochloride 20 mg/kg, xylazine hydro-

chloride 2 mg/kg, and atropine sulfate 0.04 mg/kg), intubated, and ventilated with either room air or 100% oxygen. A 14-F sheath was introduced into the common femoral vein as a conduit for the clot. A catheter was also inserted into the common femoral artery to allow monitoring of oxygenation, pulse rate, and blood pressure. Five milliliters of blood was drawn from the femoral vein. Thrombi, histologically similar to those formed in vivo, were first produced in a modified Chandler device (9). The thrombi were cut into small pieces, 8 mm in diameter and 15 mm long, to approximate small emboli. The clots were then flushed through the sheath and into the inferior vena cava with saline solution. After that, the animals were transported from the animal preparation facility to the MR imaging suite for experiments.

Image Analysis

a.

b.

Figure 3. Pig 1. Time courses of SI changes show normal (䊏) and abnormal (䊊) results on (a) ventilation coronal RARE MR images (5,000/4.2) and (b) perfusion coronal FLASH MR images (3.0/0.9). The curves are shifted along the vertical axis for better visualization.

a.

b.

Ventilation imaging.—Forty to 80 coronal images were acquired per section while the pigs were ventilated alternately with room air and 100% oxygen. Ventilation maps were created as the difference in SI between the oxygen-enhanced and roomair images. The SI in the difference map was calculated for each pixel as SI ⫽ SIpost ⫺ SIpre, where SIpre represents the averaged SI from images acquired during ventilation of room air and SIpost represents the averaged SI from images acquired during 100% oxygen. The SI difference-tonoise ratio was measured as (SIpost ⫺ SIpre)/ ␴n, where ␴n is the SD of background noise in the subtracted image. Dynamic SI changes versus time were plotted for regions of interest (ROIs) placed (D.L.L.,

c.

Figure 4. Pig 4. Atelectasis caused by airway obstruction. (a) T1-weighted coronal MR image (5,000/4.2) shows the inflated balloon (arrow) and elevated SI distal to the balloon in the right lower lobe (arrowheads). (b) T2-weighted coronal MR image (3,000/4.3) and (c) intermediate-weighted coronal MR image (5,000/4.2) show the same anatomic abnormality (arrowheads). Volume 213 • Number 3

Ventilation-Perfusion MR Imaging of Pulmonary Disorders • 873

MR Ventilation and Perfusion SI Enhancement in Seven Animals: Comparison between Normal and Abnormal Lungs Ventilation MR Imaging Pig No. 1 2 3 4 5 6 7 Mean

Perfusion MR Imaging

ROI

SIpre

SIpost

Percentage Change

SIpre

SIpost

Percentage Change

Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal

219.3 ⫾ 29.2 293.7 ⫾ 25.5 487.0 ⫾ 105.5 631.4 ⫾ 95.8 232.8 ⫾ 29.0 222.0 ⫾ 21.3 583.0 ⫾ 84.0 1,089.2 ⫾ 84.1 484.9 ⫾ 63.1 619.6 ⫾ 19.9 224.0 ⫾ 26.8 196.6 ⫾ 19.8 667.2 ⫾ 103.2 682.4 ⫾ 140.2 ··· ···

311.9 ⫾ 21.0 297.2 ⫾ 25.8 630.1 ⫾ 75.8 672.3 ⫾ 83.1 320.9 ⫾ 27.6 228.6 ⫾ 40.6 722.6 ⫾ 76.6 1,089.8 ⫾ 100.7 588.4 ⫾ 50.6 626.0 ⫾ 15.0 343.7 ⫾ 4.7 206.7 ⫾ 18.5 839.6 ⫾ 82.6 708.8 ⫾ 141.2 ··· ···

42.2 1.2 29.4 6.5 37.8 3.0 23.9 0.1 21.3 1.0 53.4 5.1 25.8 3.9 33.4 ⫾ 11.6 3.0 ⫾ 2.4

53.0 ⫾ 6.0 44.0 ⫾ 5.0 44.9 ⫾ 4.9 47.5 ⫾ 4.1 40.6 ⫾ 7.9 83.4 ⫾ 16.4 104.1 ⫾ 7.9 200.2 ⫾ 9.6 166.5 ⫾ 17.6 171.8 ⫾ 21.9 66.1 ⫾ 7.4 94.6 ⫾ 20.8 86.7 ⫾ 8.9 80.1 ⫾ 8.1 ··· ···

385.0 ⫾ 15.0 71.0 ⫾ 6.0 190.8 ⫾ 16.7 76.1 ⫾ 4.2 190.7 ⫾ 28.7 124.9 ⫾ 20.9 251.5 ⫾ 10.9 436.0 ⫾ 8.3 605.8 ⫾ 68.9 318.7 ⫾ 24.1 396.6 ⫾ 22.0 130.1 ⫾ 14.8 413.7 ⫾ 12.2 95.3 ⫾ 12.3 ··· ···

626.4 61.4 324.9 60.2 369.7 49.8 141.6 117.8 263.8 85.5 500.0 37.5 377.2 19.0 372.0 ⫾ 157.1 61.5 ⫾ 32.3

NOTE.—Data are the mean ⫾ SD. SIpre ⫽ SI before administration of oxygen for ventilation MR imaging or gadopentetate dimeglumine for perfusion MR imaging. SIpost ⫽ SI after administration of oxygen or gadopentetate dimeglumine. Percentage change ⫽ (SIpost ⫺ SIpre)/SIpre ⫻ 100.

a.

b.

Figure 5. Pig 4. (a) Ventilation coronal RARE MR image (5,000/4.2) shows expected ventilation defect (arrowheads) in the lower lobe of the right lung. (b) Perfusion coronal FLASH MR image (3.0/0.9) shows perfusion abnormality (arrowheads).

D.K.) in the normal and abnormal lungs. Normal lung was identified as regions with uniform SI enhancement and abnormal lung as regions with no or little enhancement. The percentage SI enhancement was calculated as (SIpost ⫺ SIpre)/SIpre ⫻ 100 in both normal and abnormal lungs. Perfusion imaging.—Twenty-four to 36 coronal images were acquired after the bolus injection of gadopentetate dimeglumine. The image with peak SI enhancement in normal lung tissues was selected to show the contrast between the normal and abnormal lungs. The time course of SI enhancement was determined from the set of images with analysis software (OSIRIS,version 3.1; University Hospital of Geneva, Switzerland). With this software, 874 • Radiology • December 1999

the SI of any pixel can be evaluated for the set of images obtained. SI versus time was plotted for ROIs placed (D.L.L., D.K.) in the normal and abnormal regions of lung. The percentage SI enhancement in both normal and abnormal lung was calculated as (SIpost ⫺ SIpre)/SIpre ⫻ 100, where SIpre was obtained from a selected ROI on one of the images acquired before the arrival of contrast agent and SIpost from the image that showed maximum SI enhancement in the normal lung tissues.

Ex Vivo Pulmonary Angiography and Pathologic Evaluation Ex vivo pulmonary angiography was performed to depict the filling defects in

Figure 6. T1 curves for normal (䊏) and abnormal (䊉) lungs on coronal RARE MR images (8,000/4.2). The data were fit to the equation SI(TI) ⫽ A ⫺ B exp(⫺TI/T1), where TI is inversion time, to extract T1 values (solid lines). The small difference in T1 values between the normal and the collapsed lung suggest that lung collapse had no effect on T1 and that the SI changes are primarily related to increased proton density.

pulmonary arteries and perfusion deficits distal to the emboli, which were later compared (D.L.L., D.K. in consensus) with those findings from MR imaging. Pulmonary angiography was performed after thoracotomy, with removal of the heart and lungs. The clamped pulmonary artery was injected with a 15-mL solution of diatrizoate sodium and radiographed in the anteroposterior plane and both Chen et al

a.

b.

Figure 7. Bar graphs depict SI percentage changes on (a) ventilation coronal RARE MR images (5,000/4.2) and (b) perfusion coronal FLASH MR images (3.0/0.9) in normal and abnormal lungs. The substantial differences between normal and abnormal lungs indicate that the MR techniques used in the current study are feasible to detect regional changes in pulmonary ventilation and perfusion. Error bars indicate SD.

Figure 9. Pig. 6. 1–12, Dynamic perfusion coronal FLASH MR images (3.0/0.9) of the lung were acquired after bolus injection of gadopentetate dimeglumine, with the same window level setting. Perfusion defects (arrows in part 3) in regions distal to pulmonary emboli are clearly identified.

oblique planes. Pathologic sectioning of the lung was used to confirm the existence of pulmonary emboli. Each lobe was carefully removed from the hilum and sectioned at 3-mm intervals, transverse to the orientation of the bronchi and arteries. The presence and location of the clots were documented. Volume 213 • Number 3

RESULTS Airway Obstruction Model For all seven animals, both ventilation and perfusion abnormalities were readily observed in regions of lung supplied by the occluded airway. For the six animals

Figure 8. Pig 2. Photograph of gross pathologic specimen shows multiple emboli (arrows) in the right lung of a pig. The lung was sliced at 3-mm intervals.

in which the MR experiments were performed immediately following airway obstruction, the abnormalities were present only with ventilation and perfusion imaging techniques. The T1- and T2-weighted anatomic images were normal. For the remaining animal, abnormalities were seen on all images. Abnormal SI within the collapsed lung was seen on the T1and T2-weighted anatomic images. Results from one of the six pigs without postobstructive atelectasis are shown in Figures 1–3. In this animal, the right lower lobe bronchus was obstructed by using an occlusion balloon (Fig 1a). The T1- and T2-weighted images did not reveal any abnormality (Fig 1). However, a ventilation defect distal to the occluded bronchus was readily detected (Fig 2a) as was a matched perfusion defect due to hypoxic vasoconstriction (Fig 2b). No oxygen-related SI change was detected in the region distal to the obstruction, whereas substantial SI change was observed in other portions of the lung (Fig 3a). Decreased perfusion SI was also clearly seen in the abnormal region in comparison with normal regions (Fig 3b). For the animal with postobstructive lobar collapse (pig 4), the atelectatic lung tissue showed an elevated SI on all anatomic images (Fig 4). Additionally, the SI on perfusion images in the abnormal region was brighter, possibly owing to increased vascular density within the col-


lapsed lobe (Fig 5b). A ventilation defect was still clearly identified in the abnormal region distal to the obstructed bronchus (Fig 5a), even though the lung morphology had been altered dramatically. Interestingly, the T1 value in the abnormal region was not altered by the collapse of the lung. This is illustrated in Figure 6, in which lung SIs acquired with the inversion-recovery technique are plotted against the inversion time. After the experimental data were fitted to the T1 relaxation equation, SI(TI) ⫽ A ⫺ B exp(⫺TI/T1), the T1 values for the normal and abnormal lungs were 1,499 msec ⫾ 16 (mean ⫾ SD) and 1,530 msec ⫾ 46, respectively. The difference is within the SD of our measurement, suggesting that lung collapse had no effect on T1, and that the SI changes were primarily related to increased proton density. The Table summarizes the MR ventilation and perfusion SI changes for ROIs placed in normal and abnormal lungs. For ventilation data, all animals showed substantially higher SI changes in the normal lung (33.4% ⫾ 11.6 vs 3.0% ⫾ 2.4) after ventilation with 100% oxygen. For perfusion data, six of the seven animals displayed tremendous SI enhancement (263.8%–626.4%) in the normal lung, whereas much less enhancement was observed in the abnormal lung (19.0%–85.5%). For pig 4, postobstructive collapse caused the percentage SI changes in normal and abnormal lung to be much less dramatic. These findings are displayed in Figure 7 for clearer comparison.

Pulmonary Embolism Model Results at pathologic sectioning of the lungs confirmed the presence of pulmonary emboli in all six animals. For example, multiple emboli are clearly seen in Figure 8 within the arteries. Figure 9 is a series of MR perfusion images that demonstrate pulmonary embolism–induced perfusion deficits in pig 6. In this figure, part 1 was acquired immediately before the arrival of the bolus, and thus no SI enhancement is present. Parts 2–12 show the SI enhancement as the contrast material bolus passes from the inferior vena cava to the pulmonary arteries, through the lung parenchyma into the pulmonary veins, and finally into the aorta. A dynamic plot of regional perfusion is displayed in Figure 10. As expected, peak SI enhancement in the left main pulmonary artery preceded that in the left main pulmonary vein, with peak aortic enhancement following shortly thereafter. 876 • Radiology • December 1999

a.

b.

Figure 10. Pig 6. SI enhancement following bolus injection of gadopentetate dimeglumine on (a, b) coronal FLASH MR images (3.0/0.9). In a, time courses of the SI changes show peak enhancement of 780% and 744% for ROIs placed in the left main pulmonary artery (PA) and left lower lobe pulmonary vein (PV), respectively. In b, time courses of the SI changes show averaged peak enhancement of 540% for the four ROIs placed in normal lung tissues: LM ⫽ left middle lung, LU ⫽ left upper lung, RM ⫽ right middle lung, RU ⫽ right upper lung. Reduced peak enhancement of 440% is observed in the right lower lung (RL), and little SI enhancement is seen in the left lower lung (LL).

Peak enhancement values of 780% and 744% were observed for ROIs placed in the left main pulmonary artery and vein, respectively (Fig 10a). For lung parenchyma, the time course of the SI changes showed an average peak enhancement of 540% for the ROIs placed in normal lung tissues (right upper, middle, and lower lung and left upper and middle lung). Reduced peak enhancement of 440% was observed in the right lower lung, distal to a nonocclusive embolus, and little SI enhancement was seen in the left lower lung, distal to an occluding thrombus. The ventilation images obtained in the

same animal showed no abnormalities. There is homogeneous SI enhancement throughout the ventilated lungs, as illustrated in Figure 11, parts a–c. Perfusion abnormalities, on the other hand, are clearly depicted at the right and left lung bases (Fig 11, parts d–f). This mismatch between ventilation and perfusion reflected the vascular origin (pulmonary embolism) of the perfusion defects. This pattern (perfusion defects with normal ventilation) was observed for all animals. Typically, oxygen-enhanced ventilation SI changes ranged from 40% to 110% for both normal and diseased regions of the Chen et al

abnormal regions of lung in response to oxygen inhalation (Fig 12a), little perfusion SI change was detected in the abnormal lung distal to an embolus in the lower left lobe (Fig 12b). When MR results were compared with those obtained at ex vivo pulmonary angiography, a good match was observed between the two sets of data. For example, Figures 11 and 13 display findings from the same animal with the two imaging modalities. MR perfusion images (Fig 11, parts d–f) obtained at different section locations clearly revealed the same perfusion deficits as did pulmonary angiograms (Fig 13). The right lower lobe of this animal was still well perfused, despite the presence of multiple nonocclusive emboli in the right lung. This partially perfused region was identified on both pulmonary angiograms (eg, Fig 13a) and MR images (eg, Fig 11, part e).

DISCUSSION Figure 11. Pig 6. Ventilation-perfusion mismatch obtained in a pig model of pulmonary embolism. a–c, Ventilation coronal RARE MR images (5,000/4.2) show normal ventilation for both lungs. d–f, Perfusion coronal FLASH MR images (3.0/0.9) show perfusion defects (arrows) distal to pulmonary emboli.

a.

b.

Figure 12. Pig 6. Ventilation-perfusion mismatch shown in time courses for SI changes in ROIs placed in normal (䊏) and abnormal (X) areas of the lung on dynamic MR images. (a) Ventilation SI changes after oxygen inhalation on coronal RARE MR images (5,000/4.2). (b) Perfusion SI changes after bolus injection of gadopentetate dimeglumine on coronal FLASH MR images (3.0/0.9). These results suggest that the existence of pulmonary embolism does not alter pulmonary ventilation noticeably.

lung, whereas perfusion SI enhancement of 350%–540% was detected in normal lung parenchyma. Little or greatly reduced perfusion SI change was detected in regions distal to pulmonary emboli. Volume 213 • Number 3

The time course of the SI changes for MR ventilation and perfusion in this animal is displayed in Figure 12. Although ventilation images showed almost identical changes in SI for both normal and

The primary function of the lung is to allow gas exchange between the airways and the blood. Integral to this task is the matching of local alveolar ventilation and pulmonary blood flow. The ability to evaluate regional ventilation and perfusion is important in the assessment of lung disease. At this time, few radiographic methods exist. Nuclear medicine studies can be performed to evaluate regional ventilation and perfusion, but these studies are limited by poor spatial and temporal resolution. They also require the administration of radioactive materials. Traditional pulmonary function tests, such as spirometry or the determination of pulmonary diffusion capacity, evaluate the lung as a whole. These tests are incapable of identifying the magnitude and distribution of disease on a regional basis. Although computed tomography is an accurate method for the detection of regional morphologic abnormalities, (10,11) it does not provide a direct functional assessment of the lung. The use of MR imaging for the evaluation of pulmonary disease has been limited. The unique composition of lung tissue makes it one of the most difficult organs to evaluate with MR imaging. Little or no SI can be detected with conventional spin-echo or gradient-echo sequences owing to the low proton density of the lung. Additionally, local magnetic field gradients around the air-filled alveoli rapidly dephase transverse magnetization, which leads to SI loss (12). Cardiac and respiratory motion also create arti-


facts with conventional MR imaging techniques. To image the lung successfully, new approaches are needed to address these issues. One approach is the use of inhaled 129Xe or 3He for ventilation MR imaging (13,14). These noble gases can be hyperpolarized by using optical pumping techniques prior to MR studies. MR SI from these noble gases may be increased by 100,000 times compared with that in a thermal equilibrium state. Such strong SI provides the means for direct data acquisition with the inhaled gases, thus making lung imaging of the airways possible. Excellent results have been achieved in both animal and human studies (15–19). Although highly promising, these methods also have disadvantages. Among them are the high cost of the apparatus for gas polarization and the need for special MR imaging hardware. Furthermore, to our knowledge, the administration of these gases in severely ill patients has not been evaluated for safety. We have taken a different approach for functional MR imaging of the lung. We addressed the fundamental difficulties of lung imaging by developing new imaging techniques that are fast, have high signalto-noise ratio, and are insensitive to local magnetic field inhomogeneities. For example, the use of a single-shot turbo spin-echo sequence for ventilation MR imaging greatly reduces the effect of local magnetic field inhomogeneity and motion artifacts (5,20). Similarly, the use of FLASH sequences with short echo time (0.9 msec) for perfusion MR imaging overcomes the short T2* of lung tissue (7). By implementing these MR techniques, we have accomplished pulmonary ventilation and perfusion MR imaging with oxygen and gadopentetate dimeglumine, respectively, as contrast agents (4–7). The perfusion sequence balances temporal resolution with the amount of lung imaged. For example, a temporal resolution of less than 300 msec can be obtained for a single-section acquisition. However, the current study used a multisection acquisition with a temporal resolution of 2–3 seconds for any given section. The overall coverage of 60 mm in the coronal plane was sufficient to image the majority of the lung in the animal models. Greater coverage could be obtained, if necessary, by means of further reduction in temporal resolution or administration of additional contrast material. The duration of the sequence was sufficient to allow evaluation of both the first pass of contrast medium and recirculation. 878 • Radiology • December 1999

a.

b.

Figure 13. Pig 6. (a, b) Ex vivo pulmonary angiograms show multiple emboli (arrowheads) and perfusion defects (arrows).

The centrically reordered phase-encoding scheme in ventilation MR imaging greatly improved signal-to-noise ratio. A 2.5-fold increase in signal-to-noise ratio is observed when images obtained with this technique were compared to those obtained with the regular half-Fourier RARE sequence (21). The short effective time of 4.2 msec resulted from the centric-reordering method, which maximized the signal contribution from tissue with short T2 in the lung. However, this is at the expense of image quality and spatial resolution. First, the discontinuity of MR signals at the center of k space causes image blurring. Second, owing to the long acquisition time for each image (538 msec) and short T2 values in the lung, the later echoes are basically noise. When these echoes are placed at the outer k space, high-spatial-resolution information is lost. These issues should be addressed in future studies. Findings in the current study clearly demonstrate the ability of MR imaging to depict both regional pulmonary ventilation and perfusion. In the model of airway occlusion, a mean 11-fold increase in ventilation SI enhancement was seen in the normal lung compared with that in the obstructed lung. This suggests that the use of oxygen as an MR contrast agent is a sensitive method for the evaluation of regional ventilation impairment. In the same experiment, MR perfusion imaging showed an associated decrease in perfu-

sion SI enhancement in the obstructed lung. This likely reflects hypoxic vasoconstriction. The ability to image basic functions of the lung with this precision is promising. The current study evaluated changes in ventilation associated with the occlusion of large airways. The ability of this technique to demonstrate smaller regions of nonventilated lung has not yet been tested. However, both the spatial and contrast resolutions of this technique appear to be sufficient to allow imaging of smaller regions of airway obstruction. Although the ventilation images were obtained in mechanically ventilated animals, the same sequence has been used successfully in healthy volunteers and patients, with a face mask and oxygen flow rates of 10–15 L/min (4,5). In the model of pulmonary embolism, mismatched ventilation and perfusion patterns were observed in all animals. Perfusion defects were seen in regions distal to the thrombi, whereas no ventilation abnormalities were detected in any animals. The application of ventilationperfusion MR imaging to the assessment of pulmonary embolism in the current study was based on the concept developed in nuclear medicine that the overall diagnostic accuracy of radionuclide scintigraphy is substantially improved when findings from ventilation studies are combined with those from perfusion studies (22). Mismatched ventilation-perfusion Chen et al

abnormalities (reduced perfusion with normal ventilation) suggest a high likelihood of pulmonary embolism, whereas perfusion defects accompanied by abnormal ventilation are unlikely to represent pulmonary emboli. This was seen in the model of airway occlusion, in which perfusion abnormalities were identified that were not related to a vascular origin. This concept has also been applied recently to a rat model of pulmonary embolism with MR imaging by Berthezene et al (1). In their study, pulmonary ventilation was assessed with aerosolized gadopentetate dimeglumine as a T1 contrast agent, and pulmonary perfusion was assessed with intravenous administration of polylysine(gadopentetate dimeglumine) 40. Their results confirm that simultaneous assessment of ventilation and perfusion improved the specificity of contrast material– enhanced perfusion MR imaging. Practical applications: MR ventilation and perfusion imaging may have a major impact on the evaluation of a variety of pulmonary disorders. Although the methods in this study were used to evaluate animal models of disease, we have used these same techniques to evaluate ventilation and perfusion in human volunteers and patients (4,5,23). The evaluation of pulmonary embolism with MR perfusion and ventilation techniques has been used on a limited basis at our institution. Combined with pulmonary MR angiography, the methods can demonstrate both perfusion defects and the accompanying emboli. In the animal models, segmental and subsegmental perfusion defects were clearly identified. Whether MR perfusion techniques will allow accurate assessment of subsegmental emboli in patients will require further study. Additionally, difficulties may arise from the presence of concomitant lung disease. As seen in the current study, the presence of atelectatic lung altered the SI of the parenchyma. Whether this will reduce the detection of small emboli will need to be evaluated in a clinical setting. The use of blood-pool MR contrast agents may further improve detection of small emboli by increasing the contrast between the intravascular space and the pulmonary interstitium. The value of these techniques in other

Volume 213 • Number 3

pulmonary disorders is unknown. Clearly, alterations in regional pulmonary ventilation and perfusion play a major role in the development of hypoxemia associated with pulmonary disease (24). Studies are currently underway to examine the clinical value of these techniques in patients with various pulmonary diseases, such as pulmonary emphysema. In conclusion, our results show that it is feasible to use MR imaging to evaluate lung function on a regional basis. This ability to demonstrate differences in regional lung function in the absence of a structural abnormality may provide an important tool for the evaluation of patients with pulmonary disease and may eventually provide quantitative regional indexes of lung function. References 1. Berthezene Y, Vexler V, Clement O, Muhler A, Moseley ME, Brash RC. Contrastenhanced MR imaging of the lung: assessments of ventilation and perfusion. Radiology 1992; 183:667–672. 2. Middleton H, Black RD, Saam B, et al. MR imaging with hyperpolarized He-3 gas. Magn Reson Med 1995; 33:271–275. 3. Albert MS, Cates GD, Driehuys B, et al. Biological magnetic resonance imaging using laser-polarized Xe-129. Nature 1994; 370:199–201. 4. Edelman RR, Hatabu H, Tadamura E, Li W, Prasad PV. Noninvasive assessment of regional ventilation in the human lung using oxygen-enhanced magnetic resonance imaging. Nat Med 1996; 2:1236– 1239. 5. Chen Q, Jakob PM, David V, et al. Oxygen enhanced ventilation MRI of the human lungs (abstr). In: Proceedings of the Fifth Meeting of the International Society for Magnetic Resonance in Medicine. Berkeley, Calif: International Society for Magnetic Resonance in Medicine, 1997; 181. 6. Hatabu H, Gaa J, Kim D, Li W, Prasad PV, Edelman RR. Pulmonary perfusion: qualitative assessment with dynamic contrastenhanced MRI using ultra-short TE and inversion recovery turbo FLASH. Magn Reson Med 1996; 36:503–508. 7. Chen Q, David V, Levin DL, et al. Ventilation-perfusion MRI of pulmonary embolism (abstr). In: Proceedings of the Sixth Meeting of the International Society for Magnetic Resonance in Medicine. Berkeley, Calif: International Society for Magnetic Resonance in Medicine, 1998; 453. 8. Haase A, Frahm J, Matthaei D, Hanicke W, Merboldt KD. FLASH imaging: rapid NMR imaging using low flip-angle pulses. J Magn Reson 1986; 67:256–266. 9. Poole JCP. A study of artificial thrombi

10. 11. 12.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

produced by a modification of Chandler’s method. J Physiol 1959; 44:377–383. Groskin SA. Emphysema: fact, fiction, or just a lot of hot air? Radiology 1992; 183:319–320. Webb WR. Radiology of obstructive pulmonary disease. AJR 1997; 169:637–647. Hatabu H, Alsop D, Listerud J, Bonnet M, Gefter WB. T2* and proton density measurement of normal human lung parenchyma using submillisecond TE gradient echo MR imaging. Eur J Radiol 1999; 29:245-252. Albert MS, Cates GD, Driehuys B, et al. Biological magnetic resonance imaging using laser-polarized Xe-129. Nature 1994; 370:199–201. Middleton H, Black RD, Saam B, et al. MR imaging with hyperpolarized He-3 gas. Magn Reson Med 1995; 33:271–275. Kauczor HU, Hofmann D, Kreitner KF, et al. Normal and abnormal pulmonary ventilation: visualization at hyperpolarized He-3 MR imaging. Radiology 1996; 201: 564–568. Bachert P, Schad LR, Bock M, et al. Nuclear magnetic resonance imaging of airways in humans with use of hyperpolarized 3He. Magn Reson Med 1996; 36:192–196. Mugler JP III, Driehuys B, Brookeman JR, et al. MR imaging and spectroscopy using hyperpolarized 129Xe gas: preliminary human results. Magn Reson Med 1997; 37: 809–815. Johnson GA, Cates G, Chen XJ, et al. Dynamics of magnetization in hyperpolarized gas MRI of the lung. Magn Reson Med 1997; 38:66–71. Chen XJ, Chawla MS, Hedlund LW, Moller HE, MacFall JR, Johnson GA. MR microscopy of lung airways with hyperpolarized 3He. Magn Reson Med 1998; 39: 79–84. Hennig J, Friedburg H. Clinical applications and methodological developments of the RARE technique. Magn Reson Imaging 1988; 6:391–395. Chen Q, Jakob PM, Griswold MA, Levin D, Hatabu H, Edelman RR. Oxygen enhanced MR imaging: non-invasive assessment of regional lung ventilation. MAGMA 1998; 7:153–161. Alderson PO, Martin EC. Pulmonary embolism: diagnosis with multiple imaging modalities. Radiology 1987; 164:297– 312. Hatabu H, Gaa J, Kim D, Li W, Prasad PV, Edelman RR. Pulmonary perfusion and angiography: evaluation with breathhold enhanced three-dimensional fast imaging steady-state precession MR imaging with short TR and TE. AJR 1996; 167:653– 655. West JB, Wagner PD. Ventilation-perfusion relationships. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The lung: scientific foundations. Philadelphia, Pa: Raven, 1997; 1693–1709.
