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

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 = 10), Carbylan-SX films (n = 10), Carbylan-SX aerosolized hydrogel (n = 10), and Seprafilm (n = 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 μm thickness, P < 0.0001) at preventing adhesions. The Carbylan-SX film and Carbylan-SX aerosolized hydrogel both proved to be better at preventing adhesions than Seprafilm (Genzyme Corp., Cambridge, MA) with an average adhesion thickness of 454 and 577 μm, respectively, compared with 1319 μm 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.

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, 2, 3, 4, 5, 6, 7, 8, 9]. Duncan et al. reported the incidence of a major vascular injury occurring at resternotomy to be 2% to 6% [1, 2, 3, 4, 5, 6, 7, 8, 9, 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 the pericardial space are associated with a significantly increased morbidity and mortality. Adhesion formation has been shown to result from trauma, ischemia, foreign-body reaction, infection, and hemorrhage [12].

Several attempts have been made to reduce or prevent development of postoperative adhesions in the retrosternal space [2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 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, 26, 27, 28]. Physical barriers, including silicone, polytetrafluoroethylene, cellulose, polyvinyl alcohol, and polyester derivatives have also been developed [12, 29, 30, 31, 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, 34, 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.