A prospective, randomized, experimental study to investigate the peritoneal adhesion formation of noncontact argon plasma coagulation in a rat model

A prospective, randomized, experimental study to investigate the peritoneal adhesion formation of noncontact argon plasma coagulation in a rat model

A prospective, randomized, experimental study to investigate the peritoneal adhesion formation of noncontact argon plasma coagulation in a rat model B...

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A prospective, randomized, experimental study to investigate the peritoneal adhesion formation of noncontact argon plasma coagulation in a rat model Bernhard Kraemer, M.D.,a Ralf Rothmund, M.D.,a Klaus Fischer, Dipl.-Ing.,b Marcus Scharpf, M.D.,c Falko Fend, M.D.,c Luisa Smaxwil, M.D.,a Markus Dominik Enderle, M.D.,b Diethelm Wallwiener, M.D.,a and Alexander Neugebauer, Dr. rer. nat., Dipl.-Chem.b a Department of Obstetrics and Gynecology, University of T€ubingen, Pathology, University of T€ubingen, T€ubingen, Germany

b

Erbe Elektromedizin GmbH, and

c

Department of

Objective: To investigate the peritoneal adhesion formation of two pulsed noncontact argon plasma coagulation (APC) modes in a rat model. Design: Prospective, randomized, controlled, and blinded study. Setting: Laboratory facilities of a university department of obstetrics and gynecology. Animal(s): Ten female Wistar rats. Intervention(s): Bilateral lesions were created on the abdominal wall with low and high APC energy in a standard fashion. After 10 days the rats were killed to evaluate the peritoneal trauma sites. Main Outcome Measure(s): Adhesion incidence, quantity, and quality were scored 10 days after surgery and studied by histopathologic analysis. Result(s): The area of coagulation was 30  8.4 mm2 in the case of high APC energy and 12  5.6 mm2 (low APC energy). Macroscopic thermal damage of the peritoneum is significantly higher when applying high APC energy. Adhesions due to APC with high energy occurred in 64% and with low energy in 6% of cases. High energy results mainly in dense adhesions. The lesions in the high-energy group showed intense granulation tissue formation with centrally located myocyte necrosis with intense neutrophilic inflammation. Conclusion(s): This study describes for the first time that different noncontact APC energy settings induce peritoneal adhesions in a reproducible rat model. Higher energy produced significantly deeper tissue defects and adhesions of higher grade. A plasma coagulation system that develops fewer adhesions can be achieved by lower temperature and a more homogeneous application and if the application area desiccates more slowly. (Fertil Steril 2011;95:1328–32. 2011 by American Society for Reproductive Medicine.) Key Words: Adhesions, argon plasma coagulation, rat model, coagulation, thermal damage

Adhesions occur after peritoneal trauma inducing a complex cascade that eventually leads to connective tissue bridges forming to cover the defect. Adhesions form after both conventional and laparoscopic approaches representing a triple burden, with patients affected by significant morbidity (1), surgeons affected by the challenge of adhesiolysis (2), and the health care system affected by considerable costs (3). Experiments include different modalities for adhesion induction (4–14), of which the majority induce traumatization of the target tissue through direct contact. Argon plasma coagulation (APC) thermally devitalizes the tissue without direct contact (15). It is suitable for hemostasis and tumor devitalization in the peritoneal cavity (16). However, it has never been investigated whether certain noncontact APC energy modes Received November 19, 2010; revised January 13, 2011; accepted January 18, 2011. K.F., M.D.E., and A.N. are employees of the research department, Erbe €bingen, Germany. B.K. has nothing to disElektromedizin GmbH, Tu close. R.R. has nothing to disclose. M.S. has nothing to disclose. F.F. has nothing to disclose. L.S. has nothing to disclose. D.W. has nothing to disclose. Presented as an oral presentation at the 19th Annual Congress of the European Society for Gynaecological Endoscopy, Barcelona, Spain, September 29–October 2, 2010. Reprint requests: Bernhard Kraemer, M.D., University Hospital for €bingen, Germany D-72076 (E-mail: Women, Calwerstrasse 7, Tu [email protected]).

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have an influence on adhesion formation. This study describes a rodent model to induce peritoneal adhesions by pulsed APC in two energy settings without direct contact.

MATERIALS AND METHODS This prospective, randomized, controlled, and blinded study was approved by the Ethics Committee of the regional board in T€ubingen, Germany (registration number F 1/09), after the number of animals used to assess the hypothesized difference in adhesion formation with two different APC energies had been calculated prospectively by a statistician (Department of Medical Biometry, University of T€ubingen, T€ubingen, Germany). Randomization was done by assigning each lesion to one of the two possible APC energy settings with a computer-generated randomization list. The energy uptake was determined with use of a storage oscilloscope (LeCroy W6050A, 500 MHz; LeCroy Corp., New York, NY) to measure voltage, current, and application time, from which the energy intake can be calculated. The pathologist was blinded to the different APC energy settings.

Animals Female Wistar rats (n ¼ 10 animals) (Charles River Laboratories, Sulzfeld, Germany) with a weight range of 260 to 330 g were housed under laboratory conditions (temperature: mean 21 C  2 C SD; humidity: mean 55%  10% SD; 12/12-hour light-dark cycle). Food and tap water were freely available. Before surgery, five animals were kept per cage (1354G Eurostandard type IV cages; Tecniplast Deutschland GmbH, Hohenpeissenberg, Germany). Cages were lined with 5-  5-  1-mm wood chips (Abedd Lab & Vet Service

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GmbH, Vienna, Austria). With eight experimental lesions per animal, a total of 80 experimental lesions were created. After surgery, the animals were housed in separate cages (1291H Eurostandard type III H cages; Tecniplast Deutschland GmbH) until postoperative day 2. These cages were lined with unbleached chemical pulp (Paul Hartmann AG, Heidenheim, Germany). After postoperative day 2, five animals were kept per cage (1354G Eurostandard type IV cages; Tecniplast Deutschland GmbH). These cages were lined with 5-  5-  1-mm wood chips (Abedd Lab & Vet Service GmbH).

Operations for Adhesion Induction The procedures were performed under aseptic conditions in a dedicated microsurgical animal operating theater. Anesthesia was induced with use of inhaled isoflurane (Abbott, Wiesbaden, Germany) with the animals breathing spontaneously. Analgesia was provided with use of preoperative SC injection of buprenorphine (0.05 mg/kg). The animals were placed on a heating mat warmed to 38 C (ThermoLux Waermeunterlage; Witte þ Sutor GmbH, Murrhardt, Germany). After shaving, the surgical field was disinfected (Softasept N; B Braun, Melsungen, Germany). Sterile covers (Cardinal Health, Voisins le Bretonneux, France) were applied to the surgical field. After longitudinal midline incision on each side wall four peritoneal lesions (four lesions with low energy on one side wall, four lesions with high energy on the opposite wall ¼ eight lesions per animal) were inflicted by noncontact APC.

Technical Devices, Parameters of Setting, and Agents The modular VIO generator (VIO 300D; Erbe Elektromedizin GmbH, T€ ubingen, Germany) was used as the radiofrequency system. The applications were carried out by using the APC mode pulsed effect 2 and a power setting of 10 and 25 W, respectively. With pulsed APC effect 2, the energy is applied discontinuously in short pulses (16 pulses per second). An application time of 4 seconds was used for application of low APC energy. Four seconds is a standard application time in humans; longer times are used only for tumor devitalization. The same mode and time with a power setting of 25 W was used for application of high APC energy. The argon flow was set to 0.3 L/min. The distance between the tip of the APC probe and the peritoneum was 2 to 3 mm in all cases. A rigid APC instrument (1.5 mm in diameter, 240 mm in length, REF: 20132-112) on a stand was used to create the lesions. Lesions were photodocumented (Canon EOS

350D; Canon Inc., Tokyo, Japan). The macroscopic area of coagulation was measured with use of AxioVision LE Rel. 4.4 (Carl Zeiss MicroImaging GmbH, Jena, Germany). The midline laparotomy was closed in two layers. The musculoperitoneal layer was closed with a running suture (Vicryl 3-0; Ethicon, Norderstedt, Germany), and the skin was closed with clips (Leukoclip SD; Smith & Nephew GmbH Wound Management, Schenefeld, Germany). After surgery the animals received analgesia with buprenorphine (0.05 mg/kg) SC every 6 hours until postoperative day 2. The operations were limited to <20 minutes for each rat to minimize the effect of room air tissue drying. All operations were performed by the same surgeon (B.K.). After 10 days the rats were killed with carbon dioxide for second look. The trauma sites were photodocumented. The quantity and the quality of adhesions induced by APC were investigated according to a previously published score (13): the quantity of adhesions is expressed by the total number of adhesions originating from the lesion points. The quality is described macroscopically by subgroups: avascular, filmy vascular, dense vascular, inclusion of organs (Fig. 1). Finally, the peritoneal trauma sites were excised, fixed in 4.5% phosphate-buffered formalin, and embedded in paraffin. For histologic analysis hematoxylin-eosin and Elastica van Gieson stains were used. Calibrated photographs were taken with use of a Zeiss Axio Scope microscope (Carl Zeiss MicroImaging GmbH), a Progress C10 camera, and the Imagic Image Access software (version 6.39; Imagic AG, Glattbrugg, Switzerland). The inflammation was graded in four categories (none, minimal, moderate, and strong). All histologic specimens were evaluated blindly by the same pathologist (M.S.).

Statistics Data were collected and analyzed by means of descriptive statistics (mean and SD), as well as by statistical hypothesis testing. Comparisons between groups were performed by Fisher’s exact test for categorical variables (adhesion frequency). Student’s t-tests were used to compare normally distributed variables (coagulation area, depth of lesion) between groups. All P values (P<.05 was considered statistically significant) were two sided and were not adjusted for the number of parameters evaluated. Statistical analysis was accomplished on a computer with use of the statistic software PRISM 4.0 (GraphPad Software, Inc., La Jolla, CA).

FIGURE 1 Quality of adhesions by four-stage adhesion score. (A) Quality of adhesions due to low APC energy (four adhesions). (B) Quality of adhesions due to high APC energy (24 adhesions).

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Area of Coagulation

TABLE 1 Frequency of adhesions resulting from high energy and low energy intake by APC.

Type of adhesion Adhesion visible, n (%) Adhesion not visible, n (%) Total

High APC energy

Low APC energy

24 (66.7) 12 (33.3) 36 (100)

4 (11.1) 32 (88.9) 36 (100)

The area of coagulation was 30  8.4 mm2 (high energy) and 12  5.6 mm2 (low energy) (P<.0001). Thus, macroscopic thermal damage of the peritoneum is significantly higher when applying high APC energy. The same situation can be observed after 10 days: the average area of coagulation of high APC energy was 34  13 mm2 and 17  8.6 mm2 with use of low APC energy (P<.0001). This means an enlargement of the lesion of 13% for high APC energy and 42% for low APC energy within 10 days.

Kraemer. Peritoneal adhesions in a rat model. Fertil Steril 2011.

Adhesion Formation RESULTS The APC energy intake of low versus high energy was determined to be 45  3 J versus 109  9 J. Ten rats were used to perform 40 APC applications of high energy and 40 APC applications of low energy. Nine rats tolerated the standardized procedures and the administration of the protocol well. All laparotomy sites were intact. One rat died 2 days after surgery because of an unintended secondary injury of the small intestine by APC application with high energy causing fatal peritonitis.

Adhesions due to high energy occurred in 64% (23/36) and to low energy in 6% (2/36) of cases (P<.0001, Table 1). Thus, APC with high energy leads to significantly more adhesions. The quality of the adhesions was evaluated with use of a four-stage adhesion score (13). Figure 1 shows the distribution of the scores. In the case of low energy (Fig. 1A), there are mainly avascular and filmy vascular adhesions (75% in summary) whereas the high energy (Fig. 1B) results mainly in dense adhesions and adhesions with inclusion of intra-abdominal organs (81% in summary). Figure 2 depicts characteristic examples for all adhesion classes.

FIGURE 2 Characteristic examples for adhesion classes. (A) Avascular adhesion. (B) Filmy vascular adhesion. (C) Dense vascular adhesion. (D) Adhesions with inclusion of surrounding organs.

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Histology Histologic evaluation revealed a relation between depth of lesion and inflammation and adhesion formation: the average depth of the lesion created by high APC energy was 1,722  1,184 mm versus 574  416 mm (low energy) (P<.0001). The low-energy group showed mild to moderate granulation tissue formation and inflammation with scattered foreign-body giant cells and proliferation of the subserous fibroblasts (Fig. 3, blue bars). The high-energy group showed intense granulation tissue formation in part with centrally located myocyte necrosis with intense neutrophilic inflammation (Fig. 3, red bars).

DISCUSSION Various adhesion models have been described (4–14). They mostly are based on direct injury of the visceral or peritoneal surface by means of different mechanical traumas or contact diathermy. In contrast, APC applies contactless energy via a partially ionized argon gas flow (argon plasma) onto the target tissue. The second generation of APC provides pulsed and precise application modes with different coagulation effects (17). The pulsed mode in our experiment delivers discontinuous current. The pulsed APC mode bears the advantage of constant voltage (4.3 kV). In the case of forced APC the voltage is dependent on the power output. The lower the power output, the smaller is the voltage. With use of forced APC it is not possible to apply a power output <30 W because of ignition problems arising from insufficient height of voltage. Pulsed APC delivers a reliable ignition of the plasma already at an applied power of 1 W. Furthermore, the maximum possible distance of the APC probe (%7 mm) is larger compared with the forced APC mode (%5 mm) (15). Clinical reports of APC are increasing (18–27). Recently, the use of APC for hemostasis in the peritoneal cavity has been published (16), and the destruction of local endometriosis tissue or superficial tumor spread can be seen as possible indication. Consequently, it is

FIGURE 3 Inflammation or granulation tissue formation resulting from application of low APC energy (blue bars) and high APC energy (red bars).

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clinically relevant to define appropriate energy settings for these indications that induce the least possible adhesions per se. With use of an argon gas flow between 0.3 and 1 L/min, application time up to 4 seconds, and power settings between 20 and 80 W the depth of penetration is expected to be <5 mm. Therefore, the major advantage of APC is seen in the fact that limited damage is caused in superficial tissue layers as the current is transported to untreated areas with lower resistance, thus protecting from deep burns (28, 29). At second look we could demonstrate that the maximum depth of the lesions with both pulsed energy settings was 2,906 mm. Interestingly, after 10 days the size of the coagulated area significantly increased by 13% for high APC energy and 42% for low APC energy. This indicates that the thermal damage induced by APC is also progressive, as already previously investigated for other thermal methods (30–33); therefore, one should take into consideration not only the depth of the penetration but also the laminar spread of the thermal lesion when APC is applied adjacent to essential organs or tissue. Even though we sought to determine a fixed distance between the tip of the probe and the peritoneal tissue of 2 to 3 mm, we are aware of the fact that this distance possibly may have varied, which can be a limiting assessment factor. Whereas APC complications such as stenosis, airway fires, hemorrhage, and gas embolism (34–36) are reported in the literature, it is completely unclear whether this supposedly superficial tissue trauma promotes the formation of substantial adhesions and whether different APC energies cause adhesions of various strength and grade. Whereas previously published studies on adhesion formation are based on direct contact with the tissue, which itself can lead to adhesions, this aspect can be ignored in our study because APC transfers the current entirely without contact through a probe that is inserted in the peritoneal cavity. Here we demonstrate that, by using the same probe size, higher APC energy significantly leads to a larger and deeper coagulation area, which obviously results in a higher number and a higher grade of adhesions. This indicates that this noncontact application of energy, in contrast to direct applications, must be able comparably to activate the dynamic process of adhesion formation with antecedent fibrinous exudation, cytokine production, and suppression of fibrinolytic activity (37) in the underlying tissue. Histologically, higher APC energy led to deeper lesions, but both lower and higher energy resulted in granulation tissue formation and inflammation of variable intensity and correlating fibrinous exudation. However, the exact mechanism of how the cascade is influenced by noncontact APC remains unclear, as it still is with direct modes of monopolar or bipolar electrocautery. It is not yet fully understood whether an intense histologic inflammation pattern necessarily correlates with an increased clinical adhesion burden. Adequate scoring is a notorious problem of all studies that focus on adhesion formation. To date there is no accurate scoring system available that has proved to be significantly superior to other systems. It therefore has to be stated that a statistically significant difference in the applied adhesion score does not necessarily reflect the clinical situation or the severity of patients’ symptoms. In this study we used a score that has been published previously, and we systematically assessed the adhesion formation by one blinded investigator to reduce interobserver variability. However, we are fully aware of the previously mentioned limitations, which also count for our study. Another limitation is the use of liver tissue for the determination of the absolute energy intake of low- and high-energy APC. The impedance of liver and peritoneal tissue is different, and thus different energy intakes should be applied. However, the ratio between low and high APC energy should be the same in both types of tissue.

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For the technical advantages that were presented already in the first paragraph, we would currently recommend pulsed APC effect 2 (10– 15 W) to treat peritoneal structures, structures near the peritoneum, or organs that are in close contact with the peritoneum. Different APC energies lead to the formation of adhesions of various extents; however, to date it remains unclear whether these adhesions cause a comparable clinical burden in contrast to direct trauma of the peritoneum by cauterization or blunt and sharp surgical interventions. We therefore suggest directly comparing the adhesion formation after different peritoneal traumatization including APC as one mode in further experimental models. The challenge will then be to define energy settings in each group that make a direct comparison possible.

In conclusion, different noncontact APC energy settings induce peritoneal adhesions in a reproducible rat model. Higher energy produced adhesions in >60%, significantly deeper tissue defects, and adhesions of a higher grade. Both low and high APC energy led to traumatized areas that increased significantly over a period of 10 days. The present model can serve for further developments of APC instruments and current modes to reduce adhesions. Acknowledgment: The authors thank M. Eichner, M.D., Department of Medical Biometry, University of T€ubingen, Germany, for his assistance in the statistical evaluation of the number of animals used in this study.

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