MR-Based Temperature Monitoring for Hot Saline Injection Therapy

Transcription

1 JOURNAL OF MAGNETIC RESONANCE IMAGING 12: (2000) Original Research MR-Based Temperature Monitoring for Hot Saline Injection Therapy Shigeo Okuda, MD, 1 * Kagayaki Kuroda, PhD, 1 Koichi Oshio, MD, PhD, 1 Robert V. Mulkern, PhD, 2 Vincent Colucci, BA, 1 Paul R. Morrison, MS, 1 Osamu Kainuma, MD, 1 and Ferenc A. Jolesz, MD 1 We applied magnetic resonance (MR) phase mapping methods to monitor the thermal frequency shift of water in order to study temperature changes from percutaneous hot saline injection therapy (PSIT) using in vitro swine livers and in vivo rabbit livers. The thermal coefficients calculated from the shifts of the water frequency with thermocouple based temperature measurements were ppm/ C for the in vitro studies and ppm/ C for the in vivo studies. The error range was estimated to be 3 C and 4.5 C, respectively. Color-coded temperature maps were compared with macroscopic lesion sizes of the specimen. Regions defined using a 20 C elevation in the initial images following hot saline injection (around 55 C in absolute temperature) closely correlated with visible coagulation in size. We conclude that MR temperature monitoring of PSIT is quite feasible and may be helpful in expanding the clinical use of this thermal therapeutic tool for liver tumors. J. Magn. Reson. Imaging 2000;12: Wiley-Liss, Inc. Index terms: hot saline injection; temperature; proton thermal shift; thermal ablation; phase imaging THERMAL ABLATION THERAPY of tumors using laser, microwave, radiofrequency (RF), or focused ultrasound is one of the most exciting fields in minimal invasion therapy. The evaluation of thermal tissue change is important to improve curability and avoid harming normal tissue. Temperature monitoring is anticipated to benefit thermal therapy directly. Accurate temperature measurement during thermal ablation is important for the following reasons. First, it may be used to estimate the tissue damage caused by the heating. Second, it becomes possible to avoid undesired heating in normal 1 Department of Radiology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts Department of Radiology, Children s Hospital, Harvard Medical School, Boston, Massachusetts Contract grant sponsor: NIH; Contract grant numbers: P01 CA67165 and R01 CA Presented in part at the 7th Annual Meeting of the International Society for Magnetic Resonance in Medicine, Philadelphia, *Address reprint requests to: S.O., who is presently at the Department of Diagnostic Radiology, Keio University Hospital, 35 Shinanomachi, Shinjyuku-ku, Tokyo, Japan. shige@bwh.harvard.edu Received August 2, 1999; Accepted February 11, tissue. Thermocouple methods can provide precise temperature measurements but only at a limited number of points, making estimates of the extension of the heated area problematic. MRI has the significant advantage of allowing for a fairly complete estimate of the extent of changes due to heat. MRI parameters including T1 (1 7), T2 (2,8) and the water apparent diffusion coefficient (9,10) are related to temperature and so have the potential for use as the basis for MRI temperature measurements. However, MRI temperature monitoring based on these parameters has potential problems including tissue-dependent temperature sensitivities and the difficulty of making relaxation time measurements in short scan times. The water proton chemical shift (11 16) is also related to temperature and has the following advantages for temperature monitoring in comparison with the other parameters. First, it is possible to measure the proton chemical shift independently of the other parameters. Second, there is a well-established linear relationship between the water proton chemical shift and temperature, namely, the water frequency shifts linearly with temperature at the rate of approximately 0.01 ppm/ C or, equivalently, 0.64 Hz/ C at 1.5 T (12). Investigators have demonstrated the applicability of this proton chemical shift-based temperature monitoring for several thermal ablation therapies including laser (17), microwave (18), RF (19), and focused ultrasound (20,21). In addition to these thermal ablation methods, percutaneous hot saline injection therapy (PSIT) has been proposed as a means for tumor ablation (22). PSIT may be viewed as an alternative to percutaneous ethanol Injection therapy (PEIT), which has been widely accepted as one of the major therapies for hepatic tumor treatment. No special devices are required for PEIT except an ultrasound (US) instrument for needle guidance and observation of the ethanol distribution. PEIT is cost effective and practical from a clinical perspective, although it has some obvious limitations. PEIT utilizes the ability of ethanol to dehydrate and coagulate tumor proteins (23). The amount of injected ethanol is limited because of its harmfulness to normal tissue when it overflows from the tumor. This feature limits the curable tumor size to up to 3 cm and makes it necessary to 2000 Wiley-Liss, Inc. 330

2 MR Monitoring of PSIT 331 repeat PEIT sessions for complete tumor necrosis. The increased number of needle punctures increases potential risk factors, which include bile ductal and vascular injuries. PSIT has the potential to overcome the disadvantages of PEIT using basically the same clinical procedure but replacing the ethanol with hot saline. Saline is a human-compatible substance and is never heated to a degree which can vaporize tissue. However, PSIT has received little attention as a tumor ablation therapy. The reason is due to both the limited heat energy of the hot saline and the uncertainty of the associated heat distribution. The operator can observe the distribution of saline as a hyperechoic area with US, although this is not equivalent to a determination of the heated area. Clearly temperature monitoring may be extremely useful for improving PSIT efficacy, although there are no reports addressing the issue of temperature distributions from hot saline injections. The aim of this study was to assess the feasibility of MR temperature monitoring for PSIT using both in vitro and in vivo liver models to study the temperature distribution after hot saline injection. We also discuss the possibility of estimating tissue changes from the temperature distribution maps. To our knowledge this is the first report to apply MRI temperature monitoring techniques to PSIT. MATERIALS AND METHODS Temperature Imaging For temperature monitoring, phase images were acquired using a spoiled GRASS (SPGR) sequence. Imaging parameters were selected according to recommendations of a previous study (24): The TE was chosen to be approximately equivalent to the T2* of the tissue, and the flip angle was close to Ernst angle for the TR selected. A short acquisition time was required for high temporal resolution, and so we selected the minimum TR at the cost of the signal-to-noise ratio (SNR). Thus the following parameters were adopted for the SPGR sequence: TR/TE 40/20 msec, flip angle 30, spatial matrix , field of view (FOV) 11 cm, number of excitations (NEX) 1, and slice thickness 3 mm. Image acquisition time was 5 seconds with these parameters. The spatial resolution was 0.43 mm in the frequencyencoding direction and 0.86 mm in the phase-encoding direction. Image Postprocessing Image processing was performed off-line. The raw data were transferred to a workstation (Sparc10, SunMicrosystems, Mountainview, CA), and phase maps were reconstructed with the Matlab software package (The Math Works, Natick, MA). Phase difference maps were acquired by subtracting a reference phase map from the objective phase map. The calculation of the temperature change from the phase difference was performed as follows. Consider two sets of real ( ) and imaginary ( ) components acquired at two different time points; the phase difference ( ) in radians is obtained by calculating the arctangent of the ratio of the imaginary part to the real part (24): 1 2 tan / The chemical shift change can be calculated from the phase difference and has a linear relationship to the temperature change T ( C): 2 TE B 0 T TE where /2 is the gyromagnetic ratio, B 0 is the main magnetic field strength, TE is the echo time in seconds, and is the temperature change of the chemical shift in units of ppm/ C. The temperature change coefficient was calculated from linear regression of the temperature change measured with a thermocouple (TC) vs the phase shift measured with MRI in the case of the in vitro and in vivo studies. In Vitro Experiments We used six in vitro swine livers. A 21-G Teflon catheter was inserted into the liver for hot saline injection. Another catheter of the same size was placed parallel to the injection catheter in the same coronal plane for thermocouple placement close to the hot saline injection site. The thermocouple, consisting of a pair of copper and constantan wires (0.1 mm in diameter), was connected to a digital thermocouple reader located outside the shielded magnet room by extension cable. The temperature was continuously recorded on a video camera during the experiment. The needles were filled with room temperature saline to avoid susceptibility artifact from residual air in the catheters. This small amount of water also made it easy to locate the catheters in T2-weighted images. All MR images were acquired with a 1.5-T clinical whole-body MRI unit (Signa, General Electric Medical Systems, Milwaukee, WI). A 3-inch surface coil was placed above the specimen. The single coronal plane containing the two catheters was localized using images acquired with a RARE sequence [TR/TE 1000/144 msec, echo train length (ETL) 8], and the temperature monitoring was performed in this plane. A reference image was acquired before the syringe was attached to the catheter. Saline was heated to approximately 100 C in the shielded room. The 1-ml syringe containing 1 ml of heated saline was connected to the catheter. Immediately after the hot saline injection, SPGR images were acquired every 10 seconds throughout the first 3 minutes and then at 30-second intervals throughout the next 3 minutes. The aim of the in vitro study was to verify the accuracy of the temperature measurement during PSIT. The temperature differences were calculated in 3 3-pixel regions of interest (ROIs) near the TC tip, avoiding obvious susceptibility artifact and close to the site of the hot saline injection so that comparisons between MRand TC-based temperature differences could be made. The temperature change coefficient was calculated

3 332 Okuda et al. from these data and utilized for temperature calculation. In Vivo Experiments We used six New Zealand White rabbits for the in vivo study. The protocol was approved by the institutional internal review board. Animals were anesthetized with a combination of ketamine (33 mg/kg, Fort Dodge Laboratories, Fort Dodge, IA) and xylazine (5 mg/kg, Fermenta Animal Health, Kansas City, MO) intramuscularly. The anesthetic was added every minutes as needed to maintain the animal in a suitable condition during the procedure. A small incision was made on the abdominal wall, and the liver was pulled out. The animal was positioned supine on the scanner bed, and the exposed liver was fixed on a plexiglass plate to avoid respiratory motion artifacts. The 3-inch surface coil was placed above the liver as closely as possible. Animal respiratory motion has the possibility of displacing the objective images from the reference images even with the rabbit liver fixed to a board. Thus, prior to hot saline injection, the fixed liver was scanned and image subtraction was performed to confirm that the respiration artifact was not obvious. Two 16-G catheters were inserted into the liver horizontally along the tail-head direction. Two catheters were placed parallel to each other but separated enough (5 9 mm) to avoid drainage of injected hot saline from one catheter to the other. The imaging protocols were same as for the in vitro study. After imaging, catheters were replaced with uncooked angel-hair pasta to make landmarks for histological examination. The animal was sacrificed, and the liver lobe was excised immediately after the experiment. The specimen was preserved in formalin for 2 weeks. Each specimen was cut in the plane containing the two pieces of pasta, and the coagulated lesion was macroscopically measured. The specimen was stained with hematoxylin and eosin. The two pieces of pasta provided landmarks to confirm the correspondence between the MR images and the histological plane. RESULTS In Vitro Results The images acquired immediately before hot saline injection were found to be unsuitable as reference images for temperature mapping due to the positional movement induced by connecting the syringe. This mechanical movement caused errors in subtracted phase maps. Local tissue swelling could also result in positional errors, as observed in the axial plane in a preliminary study (data not shown). To resolve these problems, the last image of the series was used as the reference image, at which point most of the heat had dissipated. The relationship between temperature elevation as measured with the TC and the proton chemical shift for the in vitro studies is shown in Fig. 1. The error bars in this figure indicate the range of chemical shift change in the measured area. From this plot the thermal change coefficient was calculated to be ppm/ C (P 0.01) from a linear regression analysis. Profiles of the temperature elevations along one line in the phase-encoding direction that passed over the highest temperature point are provided in Fig. 2 for several different time points. Although heat dissipation with time is quite apparent, there are no remarkable changes in the shape or overall extent of the heated region. Figure 3 shows the temperature change measured with the thermocouple and that estimated from MRI near the hot saline injection site as a function of time. For this plot, the MR based temperature was calculated from the calibration data of Figure 1 and placed on an absolute scale by setting the MR based temperature equal to the TC based temperature midway through the 6 minute acquisition. Thus it is a re-representation of the data which serves to demonstrate the time dependence of the cooling effect. Error bars for the TC measurement indicate the highest and lowest TC temperatures measured during each image acquisition. The mean temperature from the 3 3 ROI is shown with MR based error bars showing the highest and lowest temperature pixels of the ROI. The temperature decreases in an exponential fashion during the course of the experiment. The temperature decreased most rapidly immediately after hot saline injection. The potential error range between MR based and TC temperature is estimated to be on the order 3 C for these in vitro studies over the range studied. In Vivo Results The TC positioning was not close enough to the injection site for meaningful comparisons of MR- vs TCbased temperature changes in several cases. For three cases we were able to obtain such comparisons. The averaged thermal change coefficient from these three studies was ppm/ C, with a standard deviation of Figure 4 shows the relationship between temperature TC measurement and the proton chemical shift for a typical in vivo case. A temperature profile is shown in Fig. 5, and temperature changes with time are shown in Fig. 6. In comparison with in vitro studies, calculated temperature has a wider deviation from the TC-based temperature because of respiratory movement. The error range of the calculated temperature was 4.5 C. Figure 7 shows a color-coded temperature map after hot saline injection. Figure 8 is a picture of the gross specimen of rabbit liver (cut in the same plane) demonstrated in Fig. 7. Two macroscopically visible tissue changes were identified, a central dense whitish change and a peripheral slightly whitish change. The sizes of dense whitish changes ranged from 3 to 10 mm. The slightly whitish change was widely distributed and extended more than 2 cm. At histology, the dense whitish change correlated to congestive degeneration (Fig. 9). This lesion is attributed to necrosis because congestive degeneration was reported as necrosis on the second or third postoperative day in previous studies with laser therapy (25,26). The slightly whitish change demonstrated edematous change. Heat-induced change occurred immediately after hot saline injection. To define the critical threshold that in-

4 MR Monitoring of PSIT 333 Figure 1. Relationship between temperature elevation measured with TC and chemical shift change from six in vitro experiments. The thermal coefficient was calculated to be ppm/ C (P 0.01) with an r value of The error bars indicate the range of chemical shift change in the measured area. The solid line is the result of the linear regression. Dotted lines show the range of upper and lower limits of the slope with P duces degeneration from the temperature maps, areas where the temperature was elevated more than 15 C, 20 C, and 25 C in the first temperature map were compared with visible degenerative changes in size. Each temperature-elevated area was measured on a color-coded temperature map, and each lesion was measured in Figure 2. Temperature profiles of a line passing over the hot saline injection site for in vitro results at the time points designated. There are no remarkable changes in the shape or overall extent of the heated region.

5 334 Okuda et al. Figure 3. Relationship between thermocouple and MR-based temperature. There is a clear correlation for the in vitro case. The potential errors are estimated as 3 C for in vitro study. length and width. The shrinkage factor occurring with specimen fixation was estimated from the ratio of the distances between the two catheters as seen in the image and the two holes measured in the fixed specimen. The shrinkage factor, however, was below detectable limitation because of the small lesion size in this study. In one case, two separated lesions were observed, and each lesion was measured independently. Fourteen data points were available for correlation between macroscopic lesion size and size measured from the temperature maps. A linear regression analysis of the two types of measurements size yielded a close correlation between 20 C temperature-elevated areas and macroscopic lesion sizes with a slope of 1.04 and an r value of 0.95 (Fig. 10). All 15 C temperature-elevated areas except one measurement were bigger than the macroscopic lesions. On the other hand, regions identified on the basis of 25 C temperature elevations underestimated the lesion size. Thus we conclude that regions associated with the 20 C temperature elevations best reflected the macroscopic changes. Since baseline temperatures were approximately 35 C, the critical threshold for tissue degeneration is estimated to be around 55 C in absolute temperature. DISCUSSION PSIT for liver tumor ablation was reported by Honda et al in 1994 (22). PSIT has the potential to become an Figure 4. Relationship between temperature elevation measured with TC and chemical shift change for one of the in vivo experiments. The thermal coefficient was calculated to be ppm/ C (P 0.01) with an r value of in this case.

6 MR Monitoring of PSIT 335 Figure 5. Temperature profiles of a line passing over the hot saline injection site for the same in vivo case presented in Fig. 4 at the time points designated. important thermal ablation therapy and provides the following advantages. The cost is low because specialized tools are not required. Saline is a human- compatible substance, and hot saline has no risk of vaporizing tissue. The saline overflowing from targeted tumor is diluted and cooled rapidly and so is less likely to harm normal tissue than PEIT, which utilizes ethanol s toxicity. Although the clinical report demonstrated the effectiveness of PSIT for hepatic tumor treatment, PSIT has not become a routine clinical tool. One reason is the uncertainty of the hot water distribution. Indeed, actual tissue temperature distributions associated with PSIT have not been addressed. For example, the coagulation ranged from 3 to 10 mm in size under similar experimental conditions in our experiments, most probably since the distribution of hot saline varied markedly as affected by the details of the blood flow in the vasculature. In addition to the report by Honda et al, Livraghi et al (27) reported saline-enhanced RF tissue ablation and concluded that saline infusion is an effective means of enlarging the heat-ablated area. No MRI temperature monitoring was utilized in that study, although they Figure 6. Relationship between thermocouple and MR-based temperature. The potential errors are estimated as 4.5 C for in vivo study. The larger error than the in vitro case is largely attributed to respiration motion.

7 336 Okuda et al. Figure 7. Color-coded temperature map in the same plane of Fig. 8. Yellow indicates a 20 C elevated area. The spatial resolutions of the x axis (phase-encoding direction) and y axis (frequency-encoding direction) are 0.86 and 0.43 mm, respectively. suggested it may be of use to be able to monitor tissue temperature distributions following saline injections. Temperature coefficients of pure water frequency shifts are approximately 0.01 ppm/ C, although ranges of this coefficient have been reported from ppm/ C for in vivo rat muscle (28) to ppm/ C for in vivo canine muscle (29). The reason for the disparate chemical shift coefficients in pure water and living animal tissue may be the presence of paramagnetic substances like deoxyhemoglobin (30). The actual tissue temperature coefficient is still a matter of controversy, especially for in vivo studies where many factors may influence the proton chemical shift. We obtained thermal coefficients of ppm/ C and Figure 9. Photomicrograph of rabbit liver after hematoxylin and eosin staining. Congestive degeneration is revealed in the dense whitish area. The surrounding slightly whitish area is edematous change (photograph not shown) ppm/ C from our ex vivo and in vivo studies, respectively. These are in fair agreement with a thermal coefficient of mouse liver reported as ppm/ C (31). To demonstrate the relationship between temperature and heat exposure time in predicting thermal tis- Figure 8. A rabbit liver specimen after PSIT. The case presented in Fig. 7 is shown in the same plane. White tissue (white arrows) is noted around a tip of pasta used to replace the catheter used for hot saline injection (arrowhead). A slightly whitish area (black arrows) surrounds the central dense white area. Another white area in the upper middle of the specimen is gallbladder fossa (*). Figure 10. Relationship between macroscopic lesion size and estimated lesion size from MRI temperature maps. The results of size estimations based on 15, 20, and 25 C temperature elevations in the first image after hot saline injection are compared. The 20 C based estimation (absolute temperature 55 C ) had the best correlation with macroscopic lesion size. The line indicates the result of a linear regression analysis with a slope of 1.04 and an r value of 0.95.

8 MR Monitoring of PSIT 337 sue injury, a mathematical model based on the Arrhenius model for chemical reaction rate has been widely used (32,33). This model shows that as the applied temperature increases, the exposure times required to produce heat injury are reduced. In PSIT, the highest temperature is achieved early, with rapid temperature decreases following. Reasoning from the Arrhenius model suggests that the initial high temperature images will thus be the most critical for predicting tissue damage. The absolute temperature 55 C immediately after hot saline injection was necessary to cause the heat induced coagulation. This threshold is slightly lower in comparison with a previous report (4), although most probably the very initial images do not capture the highest temperature achieved in practice due to the finite scan times involved. The SPGR sequence has the advantage of short acquisition times, although in its current implementation we still required 5 seconds per image. Thus, during the first image acquisition, the temperature was changing rapidly. Centric ordering of k-space lines may prove useful for solving this problem, although clearly faster image acquisitions would be beneficial for capturing the early temperature phases of the PSIT protocol. We previously reported the potential error range of MRI temperature measurements using the thermocouple method as 4.5 C in in vivo studies. This means that lesion assessment based on a 20 C elevation has the potential to involve the area between 15 C and 25 C of elevation. However, in most cases, the error is not as obvious as shown in Fig. 7. In our experiments, we used a small amount of hot saline, such as 1 ml, and we could only make small tissue changes because of the limited size of the rabbit s liver. Future studies are necessary for evaluating accuracy in larger lesions induced with more hot saline. CONCLUSIONS We applied the proton frequency thermal shift MR temperature measurement to PSIT. 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