Postoperative Pericardial Adhesion Prevention Using Carbylan-SX in a Rabbit Model

Journal of Surgical Research 140, 237–242 (2007) doi:10.1016/j.jss.2007.03.014

Postoperative Pericardial Adhesion Prevention Using Carbylan-SX in a Rabbit Model Rafe C. Connors, M.D.,1 Jeffery J. Muir, B.A., Yanchun Liu, M.D., G. Russell Reiss, M.D., Peter C. Kouretas, M.D., Ph.D., Matthew G. Whitten, M.D., Tyler K. Sorenson, B.A., Glenn D. Prestwich, Ph.D., and David A. Bull, M.D. Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah Submitted for publication January 9, 2007

Introduction. The presence of dense adhesions within the pericardial space complicates reoperative cardiac surgery. Prior attempts to reduce adhesion formation after primary cardiac surgery using medications or biomaterials have had variable success. Carbylan-SX (Carbylan Biosurgery Inc., Palo Alto, CA) is a hyaluronan-based biomaterial, which has been shown to be effective at reducing adhesions in a nonthoracic rat model. This study evaluates whether Carbylan-SX can effectively reduce postoperative adhesions within the pericardial cavity. Methods. Thirty-eight New Zealand white rabbits underwent a left lateral thoracotomy. A pericardiotomy was made and epicardial adhesions were induced on the anterior surface of the heart using a Dremel device (Racine, WI). The rabbits were divided into four groups: controls with abrasions only receiving no treatment (n ⴝ 10), Carbylan-SX films (n ⴝ 10), Carbylan-SX aerosolized hydrogel (n ⴝ 10), and Seprafilm (n ⴝ 8). The pericardial sac and chest were subsequently closed. Rabbits were sacrificed at a mean of 15 days. For histological analysis, each heart was divided into 12 separate 1 mm sections. Computer imaging software was used to measure the adhesion thickness and the mean of 12 random measurements for each animal was recorded and statistical analysis performed. Results. Histological analysis revealed all treatment groups to be significantly better than the control (2159 ␮m thickness, P < 0.0001) at preventing adhesions. The Carbylan-SX film and Carbylan-SX aerosolized hydrogel both proved to be better at preventing adhe1 To whom correspondence and reprint requests should be addressed at Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine, 30 North 1900 East, Rm 3C 145 SOM, Salt Lake City, UT 84132. E-mail: rafe.connors@ hsc.utah.edu.

sions than Seprafilm (Genzyme Corp., Cambridge, MA) with an average adhesion thickness of 454 and 577 ␮m, respectively, compared with 1319 ␮m for Seprafilm (P < 0.0001 and P < 0.0005, respectively). The Carbylan-SX film and Carbylan-SX aerosolized hydrogel were equally effective at preventing adhesion formation. Conclusion. Carbylan-SX film and Carbylan-SX aerosolized crosslinkable hydrogel are equally effective methods of reducing postoperative pericardial adhesions within the pericardial cavity. Both the Carbylan-SX film and aerosolized hydrogel showed a significantly greater reduction in adhesions than Seprafilm. Clinical application of Carbylan-SX could have significant therapeutic implications in the future. © 2007 Elsevier Inc. All rights reserved.

Key Words: retrosternal adhesions; pericardial adhesions; adhesion prevention; Carbylan; Seprafilm.

INTRODUCTION

The development of postoperative adhesions within the pericardial space complicates reoperative cardiac surgery by obscuring anatomy and prolonging dissection. This prolonged adhesiolysis may result in potential catastrophic injury to mediastinal structures. These injuries have been shown to significantly increase morbidity and mortality [1–9]. Duncan et al. reported the incidence of a major vascular injury occurring at resternotomy to be 2% to 6% [1–10]. Dobell and Jain reported the mortality rate associated with a resternotomy hemorrhage to be 39%. If the aortocoronary bypass graft is injured, the mortality rate increases to 56% [11]. While adhesion formation is a natural physiological part of wound healing, dense adhesions within the mediastinum and particularly within

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the pericardial space are associated with a significantly increased morbidity and mortality. Adhesion formation has been shown to result from trauma, ischemia, foreignbody reaction, infection, and hemorrhage [12]. Several attempts have been made to reduce or prevent development of postoperative adhesions in the retrosternal space [2–10, 13–22], as well as numerous products developed for adhesion prevention in the abdomen and pelvis [23]. Fibrinolytic agents, anticoagulants, anti-inflammatory agents, and antibiotics have been tried with variable success [24]. Several natural and synthetic physical barriers have been tried as well. Peritoneum, omentum, amnion, fibrin, gelatin, collagen, and hyaluronic acid (HA) were all tried, but never proved satisfactory [25–28]. Physical barriers, including silicone, polytetrafluoroethylene, cellulose, polyvinyl alcohol, and polyester derivatives have also been developed [12, 29 –32]. Most recently, investigational focus has turned to developing bioabsorbable antiadhesion barriers. Two commonly used such materials are Interceed (Johnson and Johnson, New Brunswick, NJ) and Seprafilm (Genzyme Corp., Cambridge, MA) These have been shown in several studies to reduce the formation of postoperative adhesions [33–35]. A new, chemically modified, in situ crosslinkable derivative of hyaluronan has shown considerable promise in a variety of in vivo models of wound repair and adhesion prevention [36]. Known as CMHA-SX or Carbylan-SX (Carbylan Biosurgery Inc., Palo Alto, CA), this material restores vocal cord viscoelasticity [37], promotes sinus [38] and middle ear [39] healing with minimal scarring or ossification, and permits damaged airways to repair with minimal stenosis [40]. In two abdominal adhesion rat models, Carbylan-SX was demonstrably superior to Seprafilm in preventing abdominal-cecal adhesions and uterine horn adhesions [41]. Carbylan-SX can be formulated either as a premade film or sprayable gel, and has been shown to work by inhibiting murine fibroblast proliferation and attachment [41,42]. Herein we describe a study designed to compare the effectiveness of Carbylan-SX film and Carbylan-SX hydrogel compared to the commercially available and clinically used Seprafilm in minimizing pericardial adhesions. MATERIALS AND METHODS Animals Forty male New Zealand white rabbits (Oryctolagus cuniculus) weighing 2.5 to 3.0 kg ordered from Western Oregon Rabbit Co. (Philomath, OR) were the subjects of this study. All rabbits were quarantined at least seven days at the Animal Resource Center (ARC) of the University of Utah. Each animal was housed individually and fed Teklad Global High Fiber Rabbit Diet (Wilmington, DE).

Materials Carbylan-S (CMHA-S), a thiol-containing derivative of HA (950 kDa, from Novozymes Biopolymers, Inc., Bagsvaerd, Denmark), was

synthesized in the Center for Therapeutic Biomaterials at the University of Utah [36]. Solutions of 4.5% (wt/vol) poly(ethyleneglycol) diacrylate (PEGDA, 3400 Da) and 2.5% (wt/vol) Carbylan-S were prepared in DPBS buffer, sterilized by filtration through a 0.45 ␮m filter, aliquoted in 1 mL/per vial, and stored in ⫺80°C freezer for future use. The Carbylan-SX gel was prepared and applied on the day of surgery in the following manner: Carbylan-S and PEGDA solutions were thawed in a 37°C water bath, mixed at a volume ratio of 4:1 (Carbylan:PEGDA), and sprayed onto the surface of the abraded epicardium. The Carbylan-SX film was prepared several days prior to surgery. The film was made as with the gels, followed by slow drying and further crosslinking. Thus, the 2.5% Carbylan-S and 4.5% PEGDA solutions were thawed in a 37°C water bath, mixed in a volume: volume ratio of 4:1, poured into a base mold (Fisher Scientific, 2 ⫻ 2 cm, 0.8 mL/mold), and allowed to dry at 37°C for three days. Seprafilm was obtained from Genzyme Corp.

Methods After obtaining approval from our Institutional Animal Care and Use Committee (IACUC), we proceeded with surgery. The night before surgery, a 25 ␮g Duragesic patch was placed on the rabbits back. Prior to surgery, they were given an i.m. injection of 0.9 mL of ketamine (25 mg/kg) combined with 0.1 mL of xylazine (4.4 mg/kg). Once adequate sedation had been achieved, an i.v. was placed and the rabbit was shaved for a left thoracotomy. Cefazolin was given for infectious prophylaxis and the rabbit was subsequently intubated using a pediatric endotracheal tube and placed on a small animal ventilator. Sedation was achieved using isoflurane and titrated by corneal reflex, heart rate, and muscle tone. Electrocardiogram leads were attached and the rabbit was positioned for a left anterior thoracotomy. The chest was disinfected with alcohol and Betadine (Fischer Scientific, Houston, TX). A left anterior thoracotomy was performed and the pericardial sac identified. The pericardium was opened longitudinally and the left ventricle was exposed. Using the Dremel device (Racine, WI) with a fine-tipped rotary sander attached, adhesions were induced by creating an abrasion on the epicardium of the left ventricle. A 6-0 prolene suture was used to mark the site of the abrasion. The rabbits were divided into four groups: Group 1 was the control and had no treatment applied to the abraded area (n ⫽ 10). Group 2 had Carbylan-SX film (1 cm ⫻ 1 cm ⫻ 1 mm) applied over the abraded myocardium (n ⫽ 10). Group 3 was treated with 1.0 mL of Carbylan-SX hydrogel (n ⫽ 10), which was sprayed over the abrasion site with a syringe connected to CO 2 gas under 40 kPA of pressure. Group 4 had Seprafilm with approximately the same dimensions as the Carbylan-SX film applied to the abrasion site (n ⫽ 8). Once the treatment had been applied, the pericardial sac and chest wall were closed with a thoracostomy tube in place. The thoracostomy tube was removed at the time of extubation. Rabbits were inspected daily by veterinary staff for postoperative complications. The rabbits were sacrificed two weeks after surgery with a lethal dose of ketamine and xylazine. The heart and pericardium were removed en bloc. The severity of the adhesions were evaluated by two blinded observers and scored as described in Fig. 1. They were subsequently taken to pathology for histological evaluation. For histological analysis, each heart was divided into 12 separate 1 mm sections. The thickness of pericardial adhesions in each group was calculated quantitatively from histological slides using computer imaging software. Statistical analysis was conducted by comparing the mean adhesion thickness between the four groups. ANOVA post hoc test (Fisher’s protected least significant difference [PLSD]) was used to compare the groups. Significance was ascribed to a P-value ⬍ 0.05. All statistical analyses were performed using STATA statistical software version 9.0 (STATA Corp., College Station, TX).

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FIG. 1. Adapted scale for subjective scoring of adhesion denseness.

RESULTS

A total of 38 rabbits survived the surgery and two week postoperative course. Rabbits were sacrificed at an average of 15 days ⫾ 1 day postoperatively. Results of the subjective analysis are shown in Table 1, with the mean for the group depicted in Fig. 2. No significant findings were seen with subjective analysis. Results of the histological evaluation, including the mean and standard deviation, for all four groups are shown in Table 2. The control group, with an epicardial abrasion only, had the thickest adhesions of all four groups with an average of 2159 ␮m. Histological analysis revealed all treatment groups to be significantly better than the control (P ⬍ 0.0001) at preventing adhesions. Histology slides depicting the adhesion thickness for each group is shown in Fig. 3. The inflammatory response was also assessed quantitatively in regards to the composition of inflammatory cells seen, although no significant difference was noted. Fibroblasts, neutrophils, lymphocytes, and macrophages were observed, but only the thickness of the adhesion varied significantly between groups. The Carbylan-SX film was significantly better at preventing adhesions than was Seprafilm with an average adhesion thickness of 454 ␮m compared with 1319 ␮m for Seprafilm (P ⬍ 0.0001). Carbylan-SX aerosolized hydrogel also proved to be better at preventing adhesions than Seprafilm with an average adhesion thick-

FIG. 2. Mean score of subjective analysis for 1: Control; 2: Carbylan-SX Film; 3: Carbylan-SX Hydrogel; and 4: Seprafilm. (Color version of figure is available online.)

ness of 577 ␮m (P ⬍ 0.0005). The Carbylan-SX film and Carbylan-SX aerosolized hydrogel were equally effective at preventing adhesion formation (P ⫽ 0.4622). Figure 4 depicts these results graphically. Results of the statistical analysis are summarized in Table 3. DISCUSSION

Our study included 38 animals divided into four different groups to evaluate the efficacy of Carbylan-SX film and hydrogel compared with no treatment or the commonly used Seprafilm. The heart was approached through a left thoracotomy, rather that a median sternotomy, to remain consistent with the model we have used in other rabbit cardiac studies where we have had excellent rabbit survival with minimal morbidity. We closed the pericardium around the treatment to mainTABLE 2 Adhesion Thickness for Sectioned Hearts

TABLE 1

Control

Seprafilm

Carbylan-SX hydrogol (␮M)

Carbylan-SX film (␮m)

1013.488 1151.708 1285.67 2419.968 2336.422 3674.46 2645.143 2404.682 2292.548 2212.371 2125.781 2349.108 2159.279 761.646

683.9797 928.5364 1577.259 1416.389 1523.34 1466.598 1251.998 1687.268 1495.307 1369.668 1165.602 1266.096 1319.337 298.736

930.313 797.7368 412.5614 438.2748 296.7521 608.7261 541.6233 246.3333 920.7238 786.5329 411.8938 531.1053 576.881 244.767

426.9841 430.674 522.6176 563.1696 444.0449 471.5464 374.8147 740.7665 515.3264 416.5444 117.3015 422.4485 453.853 150.087

Mean Scores for Each Rabbit 1 Control

2 Film

3 Gel

4 Seprafilm

4 4 3.5 2.5 0.5 3 1.5 3.5 3.5 3.5

0.5 4 3 2 2 2.5 3 3.5 3 4

4 2.5 4 4 2 1.5 2 3 3.5 3.5

4 3.5 2.5 4 4 3.5 4 3.5

Slice 1 Slice 2 Slice 3 Slice 4 Slice 5 Slice 6 Slice 7 Slice 8 Slice 9 Slice 10 Slice 11 Slice 12 Mean STDEV

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TABLE 3 Statistical Difference in Mean Adhesion Thickness Between Groups

Control versus Seprafilm Control versus Carbylan-SX hydrogel Control versus Carbylan-SX film Seprafilm versus Carbylan-SX hydrogel Seprafilm versus Carbylan-SX film Carbylan-SX hydrogel versus Carbylan-SX film

FIG. 3. Histology slides depicting the adhesion thickness for each respective group. (Color version of figure is available online.)

tain a controlled space where the greatest density of adhesions would be expected to form. While approaching the cardiac structures through a median sternotomy has been done, we would not anticipate any differences in the denseness of adhesions based only on the approach to the mediastinum. Subjective analysis, using two observers blinded to the treatments, was subsequently performed at the time of necropsy, 2 weeks following surgery. The twoweek time frame was chosen for necropsy to be consistent with prior studies, which have evaluated Carbylan-SX adhesion prevention [41], as well as the awareness that adhesions are most dense 2 to 3 weeks following surgery. Results of the subjective analysis did not show significant differences between any groups, based on the scoring scale that was adapted. Other studies using a similar scoring system have, however, shown subjective findings consistent with the objective measurements of the thickness of the adhesion. While we chose a rabbit model to use for this particular study, several

FIG. 4. Mean adhesion thickness for each group with the associated statistical outcome. (Color version of figure is available online.)

Mean difference

P-value

908.7 1582.4 1651.0

⬍0.0001 ⬍0.0001 ⬍0.0001

673.7 742.2

0.0005 0.0001

68.6

0.6943

other studies have used both sheep [16, 20, 43– 44] and canine [10, 13–19, 22] models to study methods in mediastinal adhesion reduction. These larger animal models may likely provide a more realistic model for subjective analysis on the density of the adhesions. As shown in prior studies [45– 49], we found the Seprafilm treated animals had significantly fewer adhesions than the control group, which received no treatment. More importantly, we observed that the Carbylan-SX film and hydrogel groups had significantly fewer adhesions than either the control group or the Seprafilm treated animals. When we compared the two physical forms of Carbylan-SX, the premade film and the sprayable hydrogel, we found no significant difference between the thickness of adhesions in the two groups of treated animals. Additionally, no significant difference in the number or type of inflammatory cells existed between the control or treatment groups, thus indicating none of the treatments induced an abnormal inflammatory response. Subjectively, the Carbylan-SX film seemed to degrade at a slower rate than did the Seprafilm, as we would often find some of the Carbylan-SX film in place at the time of the sacrifice 2 weeks later. This physical barrier may in part explain the improved adhesion prevention seen with the Carbylan-SX products. In regards to handling of the various products, the sprayable Carbylan-SX hydrogel had by far the most promise for ease of application in the chest. The Carbylan-SX hydrogel was prepared just before application and loaded into a syringe with a spray tip. CO 2 was used to provide pressure through a “Y” adapter and the hydrogel was sprayed onto the surface of the heart, as previously done for uterine horn and cecal abrasion models [41, 50]. Other studies have described the use of the Carbylan-SX film as being more efficacious, as suture can be used to fasten it in place [36, 41]. We found the application and repositioning of the Carbylan-SX film to be less cumbersome than Seprafilm. As seen in the clinical setting, once the Seprafilm is placed onto a moist surface, it is very difficult to reposition it, if needed.

CONNORS ET AL.: POSTOPERATIVE PERICARDIAL ADHESION PREVENTION

In summary, several attempts at reducing pericardial adhesions have been tried with varying success. Carbylan-SX film and Carbylan-SX aerosolized crosslinkable hydrogel are equally effective methods of reducing postoperative adhesions within the pericardial cavity. Both the Carbylan-SX film and aerosolized hydrogel showed a significantly greater reduction in adhesions than Seprafilm and, in our opinion, were easier to apply. Subjective evaluation of adhesion density needs further evaluation in a larger animal or human model. Clinical application of Carbylan-SX could have significant therapeutic implications in the future to help prevent injury to mediastinal structures during reoperative cardiac surgery. ACKNOWLEDGMENTS The authors, and in particular Dr. Prestwich, thank the Centers of Excellence Program of the State of Utah.

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