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Original Research |
1 VI Department of Internal Medicine, Policlinico San Matteo Foundation, IRCCS,
Piazzale Golgi, no.1, 27100 Pavia, Italy.
2 Department of Hydraulics and Environmental Engineering, University of Pavia,
Pavia, Italy.
3 Department of Physics and Chemistry, University of Pavia, Pavia, Italy.
4 Department of Surgical Sciences, Policlinico San Matteo Foundation, IRCCS,
University of Pavia, Pavia, Italy.
Received November 30, 2006;
revised April 23, 2007;
Address correspondence to S. Rossi
(s.rossi{at}smatteo.pv.it).
Abstract
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MATERIALS AND METHODS. Thermal lesions were produced in specimens of explanted bovine liver inside a hyperbaric chamber at 101 (atmospheric), 141, 202, 273, and 364 kPa using radiofrequency power settings of 20, 30, 40, and 50 W. In subsequent in vivo experiments, thermal lesions were produced in the livers of anesthetized pigs with or without occlusion of the hepatic vein draining the ablation site.
RESULTS. At each radiofrequency power setting, progressive increases in applied pressure were paralleled by decreases in minimum impedance and increases in maximum tissue temperatures at the electrode tip (reflecting tissue–fluid boiling points), delivery time, total energy delivered, and thermal lesion volumes. Similar increases were observed in radiofrequency ablation procedures performed in vivo under occlusion of the vein draining the ablation site.
CONCLUSION. By elevating the tissue–fluid boiling point, increased pressure delays the desiccation of tissue in contact with the radiofrequency electrode tip and the related sharp increase in impedance. The result is prolonged delivery of larger amounts of radiofrequency energy and larger thermal lesions.
Keywords: interventional procedures • liver neoplasms • radiofrequency ablation
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The volume of the thermal lesion created depends on the amount of heat generated within the tissue minus that lost through blood flow–related convection. Heat generation is a function of the radiofrequency power setting, the duration of energy delivery, the surface area of the conductive tip, and tissue impedance [11, 12]. At frequencies of 460–500 kHz, the resistive component of impedance depends largely on the water content of the tissue, which decreases when tissue fluids undergo vaporization and boiling. When tissues that are in direct contact with the electrode tip are completely desiccated, impedance increases sharply to levels that preclude further energy delivery [11–15].
In the beginning, the clinical applicability of radiofrequency ablation was limited by the small volume of tissue that could be ablated with a single electrode insertion [1]. Several approaches have been developed to overcome this problem including overlapping strategies [1, 2], the use of sophisticated electrodes [2–4, 14–16] that increase the amount of radiofrequency energy that can be deposited in the tissue, and finally local vessel-occlusion techniques that reduce convectional heat loss within the ablation zone [17–21].
In certain cases, the increases in thermal lesion volume produced with the latter approach have been larger than expected [19, 20]. For example, we performed radiofrequency ablation on the livers of anesthetized pigs during partial hepatic vein occlusion, which merely reduces tissue blood flow. Surprisingly, the thermal lesions produced were as large as or larger than those produced with the same equipment and power setting in explanted livers or in vivo swine livers subjected to the Pringle maneuver, conditions in which convectional heat loss is nonexistent [19]. A review of the data sets for these experiments revealed that the tissue temperatures recorded at the end of procedures performed during hepatic vein occlusion were also slightly higher than those observed during ex vivo procedures and during in vivo procedures performed under normal flow conditions or after reduction of inflow to the ablation zone.
These findings suggested that reduction of flow-related heat loss is not the only mechanism underlying the increases in thermal lesion volume achieved with hepatic vein occlusion. We hypothesized that, in addition to reducing convectional heat loss, this particular vessel occlusion maneuver also increases hydrostatic pressure in the ablation zone. The higher tissue temperatures recorded at the end of these procedures might thus reflect a pressure-induced increase in the boiling point of tissue fluids, which would delay tissue desiccation and increase the amount of energy that could be deposited within the tissue. To test this hypothesis, we first analyzed the effects of hyperbarism on the outcome of radiofrequency ablation procedures.
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In phase 2, we investigated the hypothesis that effects similar to those achieved with hyperbarism could be reproduced by occluding the vein draining the ablation zone, thereby increasing the local hydrostatic tissue pressure. We produced thermal lesions in the livers of seven live pigs (two lesions per animal): the first lesion was created in the left hepatic lobe without any blood flow manipulation (control); the second in the right lobe after occlusion of the right hepatic vein.
Equipment
The system, described in detail elsewhere
[8], included a commercially
available radiofrequency generator (TAG 100, Invatec S.r.L.) and active and
passive electrodes. The generator operates at a frequency of 480 kHz and has a
nominal power output of 100 W within an impedance range of 20–200
. Digital displays furnish real-time readings of delivered power,
duration of energy delivery, temperatures, and impedance. The active electrode
(external caliber: 1.6 mm) was a 25-cm-long stainless-steel needle, the shaft
insulated with a 0.1-mm-thick layer of plastic. The exposed tip (2.0 cm long)
contained a K-type thermocouple to monitor temperatures. It was precalibrated
with a reference Hg thermometer and had an absolute precision of ±
1.0°C within the range of 30–160°C. The passive electrode was an
8.0 x 16.5 cm conductive grounding plate (Hospital Plate, GPS).
Explanted tissues were treated inside a cylindric, stainless-steel hyperbaric chamber (height, 30 cm; external diameter, 40 cm; wall thickness, 7.0 mm) custom-built by an autoclave manufacturer (Fedegari S.p.A). A circular airtight cover, 34 cm in diameter, allowed placement and removal of tissue samples. Electrodes were introduced and withdrawn through a 10-mm-diameter gas-tight port in the chamber wall. The chamber (maximum working pressure, 800 kPa) was pressurized with compressed air introduced through a valve in the wall. Pressure was monitored with an aneroid barometer connected to an external digital display.
Radiofrequency Ablation Procedures
Ex vivo experiments were performed on specimens of bovine liver (each
weighing 270–320 g) containing no large vessels that might affect
thermal homogeneity. The tissue block (temperature range, 22–24°C)
was placed on a raised metal grid at the base of the hyperbaric chamber, and
0.9% saline solution was added until the lower surface of the tissue was
immersed to a depth of about 1.0 mm. The grounding pad was attached to the
outer chamber wall, and the tip of the electrode was inserted into the sample
through the airtight port. The chamber was sealed and isothermally pressurized
to the desired level. Radiofrequency energy was then delivered at a constant
predetermined power setting until impedance exceeded the generator's upper
limit. Each sample was used to produce a single thermal lesion.
In vivo experiments were performed on live pigs (each weighing 35–40 kg) in the laboratory of experimental surgery of the University of Pavia. The protocols were preapproved by our institutional animal research ethics commission. The procedures have been described in detail elsewhere [19]. Briefly, two grounding pads were attached to the animal's shaved back, and a midline laparotomy was performed under general anesthesia. The radiofrequency electrode tip was then inserted into the left hepatic lobe, and a control thermal lesion was created. Power was delivered at 20 W until impedance exceeded the generator's upper limits. At this point, a balloon catheter (external caliber, 2.3 mm) (C-FLEX TPE, William Cook Europe) was inserted into the right hepatic vein and advanced until its tip lay in the distal-most segment of the vein at its convergence with the inferior vena cava.
Next, an IV catheter (external caliber, 2.1 mm) (BD Angiocath, Becton Dickinson Infusion Therapy Systems) was threaded into the vein, and its tip was positioned 2.0 cm proximal to the balloon. The IV catheter was connected to a pressure monitor (Viridia M1165A, Hewlett Packard), and hepatic venous pressure monitoring was started with a standard method [23]. The balloon was then inflated with approximately 0.9 mL of saline to produce complete hepatic vein occlusion, which was confirmed by the absence of intraluminal signals on color Doppler sonography (ProSound SSD 5500, ALOKA).
When the pressure had stabilized (about 2–4 minutes after occlusion), the radiofrequency electrode tip was inserted into the right hepatic lobe, and the second thermal lesion was created with the same settings and method used for the control thermal lesion. Electrode insertions for both thermal lesions and the IV placement of the catheters were performed under sonographic guidance with the equipment cited previously and a 7.5-MHz linear probe. At the end of the procedure, the animal was sacrificed with a lethal dose of anesthetic and the liver removed for immediate examination.
Delivery time, impedance values, and tissue temperatures were recorded for each in vivo and ex vivo procedure. Voltage signals from the generator were stored in a VI Logger, USB 6008 (National Instruments) and converted into temperature and impedance signals.
Thermal Lesion Measurement
Tissue slices (4.0–5.0 mm thick), cut at right angles to the
electrode insertion line [1,
19,
24], were scanned on a
precalibrated flatbed scanner (1240U, Epson). Thermal lesions were treated as
rotational ellipsoids in which volumes are calculated as
Ve =4 /3 
Ir2 (I = 1/2
the length of the exposed electrode tip and r = radius of the largest
circular section of the thermal lesion). The radius was calculated from a
circular area (A) representing the best-fit for the central section
of the thermal lesion, so that r =(A /)0.5.
The area (A) itself was derived with the aid of the UTHSCSA
ImageTool, version 3.0 (The University of Texas Health Science Center).
Statistical Analysis
The required sample size was calculated with nQuery Advisor software,
version 4.0 (Statistical Solutions). The estimated means and SDs of the
parameters necessary to establish the sample size were based on data from the
literature
[15–19]
and the results of our preliminary experiments. Seven measurements at each
pressure (n = 5) and power setting (n = 4) were used to
ensure a power of more than 90% to detect differences with a 5% risk of alpha
error (analysis of variance).
Quantitative data are shown as means and standard errors [SE]. The Kolmogorov-Smirnov test was used to evaluate data distribution. The homogeneity of variances was assessed with the Levene test. Temperature, radiofrequency energy delivery time, total energy delivered, impedance, and thermal lesion volumes obtained at different pressures were compared by factorial analysis of variance and Scheffé post hoc tests. Correlations between parameters were analyzed with Pearson's coefficient. The thermal lesion volumes obtained at different pressures and with different amounts of energy were evaluated as means and 95% CI. Analyses were performed with Statistica for Windows (StatSoft).
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Our ex vivo experiments not only showed a clear relationship between
pressure and radiofrequency ablation outcome, they also revealed that the rate
of energy delivery plays a more important role in thermal lesion outcome than
we originally thought. The volume of a thermal lesion produced by the
deposition of a given amount of radiofrequency energy decreases as the power
setting increases. In all probability, the rapid deposition of large amounts
of energy that occurs when high power levels are used causes rapid tissue
charring that interrupts the heat diffusion process. Occlusion of the hepatic
vein draining the ablation site has a complex effect on radiofrequency
ablation. Thermal lesion volume increases achieved with this maneuver in
previous in vivo experiments
[19] and in human hepatic
tumors [21] can be partially
attributed to a reduction in convectional heat loss. Our findings suggest that
hydrostatic tissue pressure also plays an important role, albeit one that is
somewhat less straightforward than originally hypothesized. In fact, a
post-occlusion pressure of 
2.5 kPa in the hepatic vein increased the
tissue–fluid boiling point by approximately 5°C, which is consistent
with the results of our phase 1 experiments
(Fig. 1B). This increase alone
is not sufficient to justify the significant changes provoked by vein
occlusion in delivery time and minimal impedance
(Fig. 4B). However, an
increased venous pressure of 2.5 kPa would exceed interstitial pressures
(hydrostatic plus colloid osmotic pressures), reversing the pressure gradient
across the capillary wall and allowing transfer of water from the
intravascular to the interstitial space
[24].
The resulting increase in tissue water content would contribute substantially to the decreases in impedance and the increases in delivery time observed in these experiments. Occlusion of veins draining the ablation site therefore appears to increase thermal lesion volume by eliminating convectional heat loss, raising the boiling point of tissue fluids, and—above all—increasing tissue water in the form of interstitial edema. Whereas the first mechanism is operative during occlusion of vessels that either supply (i.e., hepatic artery, portal vein, and Pringle maneuver) or drain the ablation zone, the latter two mechanisms are dependent on increases in local hydrostatic pressure, which would be expected only with obstructed venous drainage. The three-pronged effect of hepatic vein occlusion hypothesized here is thus fully consistent with the relative increases in thermal lesion volume that have been observed with the different vessel-occlusion techniques [19].
The influence of pressure on thermal lesion volume has several clinical
implications. One of the most striking is that atmospheric pressure can
influence the outcome of a radiofrequency ablation procedure. Thermal lesions
produced in a sea-level city such as Venice, Italy (pressure 101 kPa),
will be larger than those created with identical equipment and settings in a
high-altitude city such as La Paz, Bolivia (pressure 64 kPa)
[22]. Intraperitoneal
pressures will also have to be considered. Pneumoperitoneum has been shown to
produce significant volume increases in thermal lesions created in pig livers
with laparoscopic radiofrequency ablation
[25]. This effect has been
attributed to decreased convectional heat loss linked to pressure-related
reduction of portal blood flow.
Our phase 1 experiments show that pressure influences thermal lesion volume even in the complete absence of blood flow and suggest that pneumoperitoneum functions like hyperbarism to increase the tissue–fluid boiling points. Pressure-related effects might also explain the larger than expected thermal lesions reported after radiofrequency ablation of small hepatocellular carcinoma nodules [4], which have been attributed to a hypothetical "oven" effect related to the insulating properties of cirrhotic tissue surrounding the tumor [26]. Our findings suggest that this phenomenon could be better described as a "pressure-cooker" effect. Small hepatocellular carcinomas are generally encapsulated [27] and have intratumoral pressures that are already higher than nonencapsulated tumors [28]. During radiofrequency ablation, the capsule would impede diffusion of gases generated by tissue heating, leading to additional increases in intratumoral pressures that could elevate the boiling point of tissue fluids.
The importance of tissue–fluid boiling points on radiofrequency ablation outcome also suggests an intriguing variety of new strategies for maximizing the volume of the thermal lesions, including those produced with microwave energy and other techniques that require the presence of water in the tissue to generate heat [29]. Thermal ablation procedures might be performed on patients inside a hyperbaric chamber, or local tissue pressures could be temporarily increased during the procedure by inflation of a balloon incorporated into the electrode, just proximal to its tip.
The pressure-induced effects on tissue–fluid boiling points could also be mimicked by physicochemical modification of tumor-tissue fluids (e.g., via intratumoral injection of a hypertonic saline solution). Indeed, we have already noted remarkably large thermal lesions when radiofrequency ablation was performed on large hepatocellular carcinomas in which arterial feeders had been embolized with gelatin sponges [20]. This phenomenon cannot be explained by the lack of convectional heat loss alone. We hypothesized that it is at least partially related to the chemical and physical characteristics of the gelatin sponges. Thanks to its water-binding proprieties [30], the presence of hydrogel in the ablation zone would promote water retention, enhance local hydration, and render tissues more resistant to desiccation, thereby increasing the amount of energy that can be delivered to the tissue.
Acknowledgments
The authors are grateful to Valentina Ravetta, Giorgia Ghittoni, Carmine
Tinelli, and Annalisa Gaspari whose important contributions to this study were
indispensable to its success. The authors also thank Fortunato Fedegari for
generously providing the hyperbaric chamber used in this study, Walter
Corsiglia and Monica Cattaneo for assistance in carrying out the experiments,
and Marian Everett Kent for valuable contributions in editing this
article.
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iæ D. Model of interstitial pressure
as a result of cyclical changes in the capillary wall fluid transport.
Med Hypotheses 2001;57
: 161–166[CrossRef][Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), 202(
), 273 (
), and
364 (•) kPa.
)
[
), and 50 W (
).
