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Experimental Studies |
1 From the Center for Devices and Radiological Health, Office of Science and Technology, U.S. Food and Drug Administration, 12725 Twinbrook Pkwy (HFZ-133), Rockville, MD 20852 (I.C., D.W.C., W.F.P., J.W.K.); and Department of Diagnostic Radiology, Special Procedures Division, National Institutes of Health, Warren Grant Magnuson Clinical Center, Bethesda, Md (I.M., B.J.W.). Received September 26, 2002; revision requested December 12; final revision received August 19, 2003; accepted September 8. Sponsored by the Department of Diagnostic Radiology, National Institutes of Health, Warren Grant Magnuson Clinical Center. Address correspondence to I.C. (e-mail: iac@cdrh.fda.gov).
| ABSTRACT |
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MATERIALS AND METHODS: The kidneys of six swine were surgically exposed. Fifteen RF ablation lesions were created in nine kidneys by using a 2-cm-tip single-needle ablation probe in varying conditions: Seven lesions were created with normal blood flow and eight were created with blood flow obstructed by means of vascular clamping (n = 5) or renal artery embolization (n = 3). The temperature, applied voltage, current, and impedance were recorded during RF ablation. Tissue-cooling curves acquired for 2 minutes immediately after the ablation were compared by using regression analysis. Lesions were bisected, and their maximum diameters were measured and compared by using analysis of variance.
RESULTS: The mean diameter of ablation lesions created when blood flow was obstructed was 60% greater than that of lesions created when blood flow was normal (1.38 cm ± 0.05 [standard error of mean] vs 0.86 cm ± 0.07, P < .001). The two methods of flow obstruction yielded lesions of similar mean sizes: 1.40 cm ± 0.06 with vascular clamping and 1.33 cm ± 0.07 with embolization. The temperature at the probe tip when lesions were ablated with normal blood flow decreased more rapidly than did the temperature when lesions were ablated after flow obstruction (P < .001), but no significant differences in tissue-cooling curves between the two flow obstruction methods were observed.
CONCLUSION: Obstruction of renal blood flow before and during RF ablation resulted in larger thermal lesions with potentially less variation in size compared with the lesions created with normal nonobstructed blood flow. Selective arterial embolization of the kidney vessels may be a useful adjunct to RF ablation of kidney tumors.
Index terms: Animals Experimental study Kidney, interventional procedures, 81.1264, 81.1267, 81.1269 Kidney, perfusion Radiofrequency (RF) ablation, 81.1269
| INTRODUCTION |
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Radiofrequency (RF) ablation is a relatively new minimally invasive image-guided tumor treatment. Although RF ablation has been used principally for the treatment of nonresectable liver tumors, in selected clinical settings it may represent an alternative to parenchyma-sparing surgery for the treatment of small renal malignancies with diameters of less than or equal to 3 cm (1317).
The combination of selective renal artery embolization and RF ablation may increase the volume of the thermal lesion and thus could be useful in the treatment of tumors larger than 3 cm in diameter. Selective embolization results in decreased blood flow, which leadsto a reduced amount of convective cooling and thus an increased extent of tissue heating. By performing selective arterial embolization, one may also decrease the possibility of hemorrhagic complications after RF ablation, which may be a greater risk with larger tumors.
We are aware of only one study of the effect of transcatheter vascular occlusion on RF ablation lesion size in the kidney. In that study, which was performed by Aschoff et al (18), the temporary balloon obstruction of renal blood flow in swine resulted in larger RF ablation lesions. Corwin et al (19) studied laparoscopic RF ablation of the kidneys with and without direct hilar occlusion in a swine model. They found that the lesions created with hilar occlusion in animals sacrificed 24 hours after the injury were larger than those created with normal blood flow. Thus, the purposes of our study were to evaluate the effect of vascular occlusion on the size of RF ablation lesions and to evaluate embolization as an occlusion method.
| MATERIALS AND METHODS |
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Procedures and Data Collection
The surgical protocol followed in this study was designed to enable access to the liver and kidneys, with the animal first placed in a left lateral decubitus position. Therefore, lesions were generated in the right kidney before the animal was turned to allow surgical exposure of the left kidney. In all cases in which multiple lesions were created in a kidney, the lesions created with blood flow were produced before vascular clamping or embolization was performed. When more than one lesion was generated in a kidney, both lesions created with normal blood flow (ie, flow lesions) and those created after blood flow obstruction (ie, no-flow lesions) were produced, with the exception of one lesion in a left kidney in which embolization was performed.
Before the ablation procedure, anesthesia was induced with an intramuscularly injected mixture of tiletamine hydrochloride and zolazapam hydrochloride (Telazol; Fort Dodge, Overland Park, Kan) plus xylazine (Phoenix Pharmaceutical, St Joseph, Mo), followed by an intravenous injection of an anesthetic combination of tiletamine hydrochloride and zolazapam hydrochloride, xylazine, atropine sulfate (AmVet, Lexington, Ky), ketamine (Phoenix Pharmaceutical), and butorphanol tartrate (Torbugesic; Wyeth, Madison, NJ); this anesthetic regimen was described by Wray-Cahen et al (20). After the animals were placed in the supine position on the table, they were intubated and mechanically ventilated. General anesthesia was maintained with 2.5%4.0% isoflurane (Abbott Laboratories, North Chicago, Ill). An author (D.W.C.) made longitudinal incisions to expose the kidneys.
A commercially available 200-W RF generator (CC1 Cosman Coagulator System; Radionics, Burlington, Mass) and a single- needle ablation probe with a 2-cm noninsulated tip (Radionics) were used without saline perfusion to create each lesion. The power was adjusted manually to maintain a temperature of 98°C at the tip of the probe for 10 minutes. To create each lesion, authors (I.M., W.F.P.) inserted the RF ablation probe through the margin of the kidney to a depth of 2 cm in either the upper, middle, or lower portion of the organ.
Blood flow was obstructed by using either vascular clamping or selective embolization. For blood flow obstruction with vascular clamping, the renal vasculature was exposed by means of blunt dissection and a loop of umbilical tape was placed around the renal pedicle. The loop was tightened by sliding a surgical suction tube over the umbilical tape to compress the vasculature and fixing the tube in place with a clamp to maintain occlusion for the duration of the RF ablation procedure and the subsequent cooling measurements (I.M., D.W.C.). For blood flow obstruction with embolization, arterial access was obtained via the femoral artery and the target renal artery was selectively catheterized with fluoroscopic guidance. The renal artery was embolized with 5001,200-µm Embosphere particles (Biosphere Medical, Rockland, Mass) (W.F.P.). The end point of embolization was the absence of blood flow at angiography. The cessation of blood flow with both obstruction methods was confirmed at Doppler ultrasonography.
The applied voltage, power, current, and calculated root-mean-square impedance were recorded during each ablation session. In addition, the temperature measured with the thermistor at the probe tip was recorded during the RF ablation and for approximately 2 minutes afterward.
The animals were euthanized by means of exsanguination immediately after the final RF ablation procedure was performed in each animal. The kidneys were removed, and the ablation lesions were bisected for gross examination. To identify the lesion margin, selected lesions were immediately placed in a 1% 2,3,5-triphenyltetrazolium chloride (red) solution for 20 minutes to stain the tissue that contained active dehydrogenase, an indicator of cell viability (21). The maximum width (perpendicular to the long axis of the RF ablation probe) and the depth of the macroscopically pale ablated area were measured by authors (D.W.C., I.M., W.F.P.).
Statistical Analyses
Analysis of variance of the lesion dimensions, RF ablation parameters, and measured temperatures was performed by using the following two comparisons: flow versus no-flow lesions and clamping- versus embolization-induced flow obstruction (ie, the two no-flow methods were compared). The applied voltage, power, current, and calculated root-mean-square impedance during the ablation, as well as the temperature measured at the probe tip during and after the ablation, also were compared. All lesions were assumed to be independent in the statistical analysis. Since the renal vasculature bifurcates early, each ablated region has an independent blood supply and should not be affected by prior ablations within the kidney. To ensure the independence of lesions in the cases in which multiple lesions were created in the same kidney, the first ablation was performed with normal flow and the second ablation was performed without blood flow.
Nonlinear regression was used to analyze the tissue-cooling curves, which indicate the temperatures measured at the RF ablation probe tip during the cooling period after ablation. A two-phase exponential decay equation was used to fit the data, and 95% CIs were constructed for each curve and its parameters. In addition, linear regressions of the first 5 seconds of each cooling curve were used to determine the initial rate of decrease in temperature at the lesion site, and the slopes of these curves were compared. All statistical comparisons were performed by using computer software (GraphPad Prism, version 3.00 for Windows; GraphPad Software, San Diego, Calif). P < .05 indicated statistically significant differences between groups. All values are reported as means ± standard errors of the means.
| RESULTS |
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| DISCUSSION |
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In the present study, the obstruction of blood flow to the ablation site resulted in mean ablation lesion diameters that were 60% greater than the diameters of lesions created in normal blood flow conditions, and there was no overlap in the ranges of lesion diameters for the two groups. These results are consistent with the results of Aschoff et al (18); in that study, perfusion was reduced by means of balloon occlusion of the renal artery. The mean sizes of lesions produced with and of those produced without vascular occlusion in the Aschoff et al study, 1.42 cm ± 0.22 and 0.80 cm ± 0.26, respectively, were comparable to the results in the current study, in which the mean lesion diameters were 1.38 cm ± 0.05 and 0.86 cm ± 0.07, respectively. These results support the application of the described blood flow obstruction techniques as a means of enhancing the RF ablation of renal lesions.
The described results may be better understood by examining the bioheat transfer equation, as originally described by Pennes in 1948 (33,34) and modified here to account for RF heating. The bioheat equation balances the accumulation of heat in tissue,
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[k
T]), convective heat loss due to perfusion (
bcb
b[Ta T]), RF heating, and metabolic heating:
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is the tissue density (in kilograms per cubic meter); c, the heat capacity of the tissue (in joules per kilogram-degrees Celsius); k, the thermal conductivity of the tissue (in watts per kelvin-meter); T, the temperature (in degrees Celsius); t, the = time;
, the gradient operator;
b, the density of blood (in kilograms per cubic meter); cb, the heat capacity of blood (in joules per kilogram-degrees Celsius);
b, the volumetric perfusion rate, expressed as the volume of blood per unit volume of tissue per unit time; Ta, the ambient temperature of the kidney (in degrees Celsius); qRF, the rate of heat generation by means of deposition of RF energy; and qm, the rate of heat generation by means of tissue metabolism.
When blood flow is obstructed,, the tissue perfusion, or
b, is zero, and, therefore, heat loss at the ablation site occurs only by means of thermal conduction, as follows:
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As the ablation proceeds, the metabolic heat source, or qm, also becomes zero in the area of coagulation necrosis.
The size of the ablation lesion in the absence of blood flow was not influenced by the method of blood flow obstruction (ie, vascular clamping or intraarterial embolization). Although the small sample size may have masked potential differences between the obstruction methods, the mean values were numerically similar and are comparable to those calculated by Aschoff et al (18). There is unlikely to be a difference in the size of the ablation lesion based on the method of blood flow obstruction. In this study, the entire kidney was embolized until no blood flow was apparent at angiography; however, subselective arterial embolization may result in the ischemia being limited to the target area while retaining the advantages of minimally invasive interventions.
The rate of cooling at the probe tip correlated with the presence or absence of renal blood flow: There was a 90% faster rate of temperature decrease with normal perfusion as compared with the temperature decrease with blood flow obstruction. When the application of RF energy is terminated, the rate of heat generation by means of RF energy deposition, or qRF, becomes zero. If blood flow is present, the bioheat equation can be simplified as follows:
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Although the perfusion, or
b, within the ablation lesion may be zero due to tissue coagulation, the perfusion of the adjacent tissues will contribute to the dissipation of heat and thus result in a higher rate of cooling, as observed in this study. Although the metabolic source value, or qm, also is expected to be zero within the ablation lesion, it still contributes to heat generation in the nonablated tissue. With the obstruction of blood flow, the bioheat equation during cooling can be further simplified as follows:
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The observed tissue-cooling curves for vascular clamping and embolization were nearly identical. This finding implies that the method used to achieve blood flow obstruction does not affect the manner in which heat is dissipated and that both flow-obstructing methods are equally effective at stopping blood flow to the lesion. The similar slopes of the initial decreases in temperature at linear regression analysis are further evidence of the similarity in cooling mechanism between the two methods of occlusion and of the slower cooling with obstruction as compared with the rate of cooling with normal blood flow conditions.
In addition to a larger lesion size, another advantage of blood flow obstruction may be the production of a more predictable lesion size. The no-flow lesion group tended to have less variation in mean diameter than did the lesions created with normal blood flow (P = .19). Further work is required to confirm this observation.
Practical applications: Obstruction of renal blood flow before and during RF ablation resulted in larger ablation lesions and potentially less variation in lesion size compared with the lesions created with normal nonobstructed blood flow. The results seen following occlusion with selective arterial embolization of the kidney vessels were similar to those seen following occlusion with renal vessel clamping. These results indicate that selective arterial embolization of tumor vasculature may be a useful adjunct to RF ablation of renal lesions. This is especially true for tumors that are large, hypervascular, or adjacent to large blood vessels. The combination of embolization and RF ablation may result in larger lesions with a potentially more predictable size, but it could also introduce new risks. Balloon occlusion could provide similar benefits with less risk to the normal parenchyma. However, permanent occlusion with embolization may better enhance tumor cell death at the margins of the RF ablation lesion owing to prolonged ischemia. Further studies of the safety and effectiveness of this combined procedure are warranted.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U.S. Food and Drug Administration, the National Institutes of Health, the Department of Health and Human Services, or the Public Health Service.
Abbreviation: RF = radiofrequency
Author contributions: Guarantor of integrity of entire study, I.C.; study concepts, I.C., I.M., W.F.P., B.J.W.; study design, all authors; literature research, I.C., I.M., W.F.P., B.J.W.; clinical studies, I.M., B.J.W.; experimental studies, all authors; data acquisition, all authors; data analysis/interpretation, I.C., I.M., D.W.C., W.F.P., B.J.W.; statistical analysis, I.C., D.W.C.; manuscript preparation and definition of intellectual content, I.C., I.M., D.W.C., W.F.P., B.J.W.; manuscript editing, revision/review, and final version approval, all authors
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