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Ann Thorac Surg 2003;76:1270-1274
© 2003 The Society of Thoracic Surgeons

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New technology

Reducing the incidence and severity of pericardial adhesions with a sprayable polymeric matrix

^a University Hospital for Cardiovascular Surgery, Berlin (Charité), Germany
^b University Hospital Heart Center, Leipzig, Germany
^c German Heart Institute, Berlin, Germany
^d German Heart Institute, San Francisco, California, USA

Accepted for publication April 23, 2003.

^* Address reprint requests to Dr Block, 2210 Jackson St, Suite 401, San Francisco, CA 94115, USA
e-mail: jonblock{at}sbcglobal.net

Abstract

PURPOSE: This study was undertaken to evaluate the antiadhesive properties of a polymeric agent in infants undergoing staged surgical correction of congenital heart abnormalities.

DESCRIPTION: Sixteen infants having staged surgical repair were treated with a polymeric matrix at the completion of the initial surgery. There were 5 untreated controls. The tenacity and extent of adhesions at five separate regions of the heart were evaluated at the follow-up surgery.

EVALUATION: For all sites combined, there was a threefold difference in median tenacity scores in favor of the experimental treatment (1.0 vs 3.0, p < 0.01). Significant differences were achieved separately at the right ventricle and the anterior surface of the great vessels (p = 0.02 for both comparisons). Analysis of adhesion scores reflecting the extent of adhesions similarly favored the experimental treatment for all sites (80 vs 270, p < 0.01), with significant differences persisting at the right atrium (p < 0.01) and the anterior surface of the great vessels (p = 0.04). There were no treatment-related adverse events.

CONCLUSIONS: Use of this polymeric agent at the completion of open cardiac surgery may prevent the occurrence or reduce the severity of pericardial adhesions.

Surgical trauma to the pericardial mesothelium during open heart procedures has the untoward consequence of depressing normal fibrinolytic activity, resulting in the formation of fibrovascular adhesions at sites of histologic and ultrastructural derangement [1]. The development of dense and tenacious adhesions makes resternotomy hazardous due to obscured anatomy and because protracted dissection and adhesiolysis increase surgical time, and may result in prolonged bleeding and possible catastrophic hemorrhage [2]. Additionally, pericardial adhesions may act to constrict the heart [3], and there is evidence implicating adhesions as a cause of right ventricular dysfunction [4] and as a factor promoting graft occlusion [5, 6].

Treatment of several congenital heart defects such as hypoplastic left heart syndrome, single ventricle anatomy, and tetralogy of Fallot often necessitates staged surgical intervention to achieve total correction in infants and children. In addition, substantive improvements in postoperative cardiac care have resulted in many adult patients surviving to become potential candidates for reoperations to repair or replace valves or to undergo additional revascularization procedures. In all these cases, the development of retrosternal or pericardial adhesions complicates reentry through a subsequent median sternotomy. A number of antiadhesive treatments have been employed with mixed success; an easy to use, safe, and effective agent is clearly needed.

A sprayable polymeric matrix, CoSeal Surgical Sealant, was granted marketing clearance by the US Food and Drug Administration in 2001 and is indicated for use in vascular reconstructions to achieve adjunctive hemostasis by mechanically sealing areas of leakage. To support this regulatory approval, findings of a randomized controlled trial have been published indicating that CoSeal offers equivalent anastomotic sealing performance compared with Gelfoam/thrombin, but it provides this desired effect in a significantly more rapid time frame [7]. More recently [2002], the identical polymeric agent (trade name, Adhibit) received marketing approval in the European Union for patients undergoing cardiac surgery to prevent or reduce the incidence, severity, and extent of postsurgical adhesion formation. The results reported in this paper supported, in part, the European regulatory clearance and provide an initial evaluation of the antiadhesive properties of this novel polymeric agent in infants undergoing staged surgical correction of congenital heart abnormalities.

Patients and methods

Patients
A study was undertaken at three German clinical centers to evaluate preliminarily the safety and effectiveness of a novel polymeric agent in reducing the incidence and severity of pericardial adhesions associated with open surgical correction of congenital heart malformations through median sternotomy. Independent ethics committees reviewed and approved the study protocol at each participating center before the initiation of this study, and informed consent was obtained from the primary caregiver in all cases. The study was conducted using Good Clinical Practice standards in accordance with the Declaration of Helsinki. Patients were recruited to participate if a staged surgical procedure including resternotomy was planned. Eleven male and 10 female infants less than 1 year of age had an initial surgical intervention within the first weeks of life, with a second follow-up resternotomy operation scheduled within 4 to 9 months.

Sixteen patients were treated with the experimental agent. Seven of these patients had hypoplastic left heart syndrome, 6 were diagnosed with single ventricle, 2 had pulmonary atresia and incomplete ventricle septum, and 1 patient presented with tetralogy of Fallot. In most cases (15/16), initial surgical palliation consisted of a Norwood procedure or pulmonary artery banding; 1 patient underwent a tricuspid valve and pulmonary artery reconstruction.

Five patients served as controls and did not receive any intervention aimed at preventing pericardial adhesions. Four of these patients had their initial surgical procedure before the initiation of this study and were scheduled for a resternotomy during the course of the study; 1 patient had surgery during the course of the study without application of the experimental agent and, thus, served as a control. One patient had hypoplastic left heart syndrome, 1 had single ventricle anatomy, 2 patients were diagnosed with a malformed atrioventricular canal, and 1 had an atrioventricular septal defect. One patient underwent a Norwood procedure, 3 patients had palliative correction of the atrioventricular canal, and 1 patient had a tricuspid valve and pulmonary artery reconstruction.

Interventions
After completion of the initial surgical procedure, experimental patients had the polymeric matrix applied at up to five regions of the heart: left and right ventricle, left and right atrium, and the anterior surface of the great vessels. The matrix was applied only to specific regions or sites where operative intervention had been undertaken. The experimental agent, Adhibit (Cohesion Technologies, Palo Alto, CA), is composed of two distinct polyethylene glycol polymers that rapidly form a biocompatible and strongly adherent hydrogel when admixed with their respective reconstitution buffers near the time of surgery. The experimental agent is applied directly to the operative site using a specially designed delivery system, forming a cohesive matrix within seconds and resorbing fully over several weeks [7–10].

Outcomes
At the time of follow-up surgery, all five regions of the heart were evaluated for postoperative adhesions. For all patients, the tenacity of adhesions was graded on a five-point scale: none (0), filmy (1), requiring blunt dissection (2), requiring sharp dissection (3), or requiring extensive sharp dissection (4). As a means of incorporating the extent of pericardial adhesions, the percentage of region covered with adhesions (eg, 25%, 50%) was combined as a product with the tenacity score to yield an adhesion score. Larger values for the adhesion score indicate more severe adhesions.

The 5 control patients had 21 sites evaluated for effectiveness; four sites were not evaluated at follow-up surgery. Among the 16 experimental subjects, 5 patients were excluded from the effectiveness analysis; 4 patients had surgical reintervention or incomplete chest closure on the initial operative day without reapplication of Adhibit. One experimental patient showed an atypical healing process with concomitant keloid formation and was excluded. The remaining 11 experimental patients had 32 sites treated with the polymeric agent at the time of initial surgical palliation and were evaluated for adhesions at follow-up; 21 additional sites also were evaluated at follow-up but were not sites of initial operative intervention and experimental antiadhesive treatment. The median time between first and second surgeries was 5 months (3 to 8 months) and 5 months (4 to 71 months) for experimental and control patients, respectively.

All 16 experimental patients and 5 control patients were included in the evaluation of postoperative adverse events, with complications graded as mild, moderate, or severe. Among experimental patients, the relationship of each adverse event with treatment was graded as definitely, likely, unlikely, or definitely not. Complications associated with adhesiolysis during follow-up surgery also were tabulated.

Statistical methods
Median tenacity scores and adhesion scores for all sites and each heart region separately were compared between study groups using the Mantel-Haenszel test and the Wilcoxon Mann-Whitney test, respectively. Due to small sample sizes, exact p values were calculated in all cases. The proportion of sites having tenacity scores of 0 or 1 was compared between study groups to the proportion of sites requiring surgical dissection (2, 3, or 4) using Fisher's exact test.

Results

The median tenacity scores for each study group are presented in Table 1 for all sites combined as well as separately for each region of the heart. Figure 1 illustrates graphically a threefold difference observed in median tenacity scores between study groups for all sites. This difference was statistically significant (p < 0.01) in favor of treatment with Adhibit. Treatment with the experimental polymeric agent uniformly provided improvement in adhesion tenacity irrespective of the region of the heart with statistically significant differences achieved at both the right ventricle and at the anterior surface of the great vessels (p = 0.02 for both comparisons). Repeating the foregoing analysis to include the additional 21 evaluated sites in experimental patients who did not undergo operative intervention and antiadhesive treatment did not alter the result measurably. For example, the median tenacity score remained the same (ie, 1.0) for all sites combined in experimental patients regardless of the increase in sample size, and the significant difference between study groups persisted (p < 0.01).

View larger version (32K): [in this window] [in a new window]   Fig 1. Distributions of median tenacity scores (left) and adhesion scores (right) by study group for all treated sites (n = 32) among experimental patients and all evaluated sites (n = 21) among control patients. Comparison of all sites between study groups favored patients treated with Adhibit for both outcomes (*p < 0.01 for both comparisons).

Four adverse events (one moderate, three severe) were reported in 3 experimental patients, including 2 deaths due to heart failure. These adverse events were judged to be definitely not related to the use of Adhibit. Three adverse events (two moderate, one severe) occurred in 2 control patients. Complications associated with adhesiolysis during follow-up surgery occurred in 2 control patients and 1 experimental patient. In controls, dense adhesions resulted in surgical damage to the superior vena cava, the right atrium, and the pericardium, as well as substantially distorted anatomy. Damage to the right atrium was sustained in a single experimental case.

Comment

It is recognized that after open cardiac surgery, the right ventricle and right atrium often become adherent to the sternum, as may the aorta and innominate vein, thereby placing all these structures at risk during resternotomy [1]. Indeed, the current study demonstrated marked adhesion formation among untreated controls at these specific anatomical regions (Tables 1 and 2). Additionally, it was at these challenging sites that the experimental polymer treatment provided the most robust efficacy in reducing adhesion tenacity and extent (Tables 1 and 2). Overall these study results with the polymeric treatment were encouraging whether examined at the most "at-risk" heart regions, overall, or on a per-patient basis.

Our primary statistical analysis used the most conservative comparisons by including only sites in experimental patients who had undergone operative intervention and antiadhesive treatment. Twenty-one additional sites were evaluated in this study group at follow-up that did not undergo surgery or treatment. A very high percentage (20/21, 95%) of these untreated sites was assigned tenacity scores of 0 or 1, confirming that adhesions rarely form in the absence of operative trauma. Consequently, including these values in the analysis substantially improved the adhesion scores in experimental patients. Unfortunately, because 4 of 5 control patients had their primary surgeries before the initiation of this study, we were uncertain as to the percentage of sites in this study group that did not sustain operative trauma. In fact, there was a fairly high percentage (9/21, 43%) of control sites assigned tenacity score values of 0 or 1 at the time of followup surgery. Thus, including all evaluated sites likely provided the most favorable result possible among untreated controls. Nonetheless, the overall study results should be considered cautiously due to the small sample of subjects studied and the lack of methodological rigor such as matching or randomization.

A number of antiadhesive interventions have been developed and many have been tested clinically in abdominopelvic applications. Unfortunately, an ideal antiadhesive treatment has remained elusive, particularly in the prevention of pericardial adhesions [3]. Pitfalls of current materials and agents include technical difficulties with surgical application, such as the need for complete hemostasis, removal of extraperitoneal fluid, and the requirement to secure some barriers with sutures that may actually promote fibrosis. Xenogeneic and synthetic pericardial substitutes also have been shown to be associated with inflammation, epicardial reaction, fibrous encapsulation, and calcification, and have not demonstrated consistent antiadhesive effectiveness [5, 6]. While systemic antiinflammatory drugs and topical application of fibrinolytic agents have been shown to reduce adhesion formation, both modalities have the untoward side effects of bruising, bleeding, and impairment of wound healing.

A novel approach to pericardial adhesion prevention has involved the application of hydrophilic polymer solutions or instillates such as dextran, polyvinylpyrrolidone, hyaluronic acid, polyethylene glycol, and related hydrogel materials. Some of these agents require continuous tissue coating before and during surgery to protect serosal and mesothelial surfaces from operative damage. Other materials, in the form of polymer films, require suturing to the pericardium. The experimental polymeric agent examined in the current study has the advantage of being applied at the completion of surgery to areas that have specifically sustained operative trauma. In many cases, the surgeon may have already used the material during the surgery to effectively seal anastomoses [7]. Additionally, this agent is nonexothermic, does not exhibit an inflammatory response or potentiate bacterial infection, adheres strongly to serosal surfaces, and does not interfere with normal wound healing [8–10]. Finally, this hydrogel chemically crosslinks to itself and to the tissues it contacts, forming a sealant to tissue fluids and an impermeable barrier to cellular ingrowth and to the histologic establishment of adhesions. Healing of the tissue along the undersurface of the hydrogel occurs normally. As the hydrogel resorbs fully over several weeks, exposed tissue surfaces have reepithelialized and are therefore no longer prone to adhesion formation [1, 9].

In many cases, the pericardium cannot be closed at the completion of open cardiac surgery and the threat of retrosternal adhesions is great. However, tenacious epicardial adhesions also can form even with primary pericardial closure. We recommend prophylactic treatment in all cases. It has been postulated that polymer coatings such as the one evaluated in this study prevent the shedding of plasminogen activator from the surgical site or reduce the access of fibrin clots to the affected serosal surfaces. Given the adhesive and mechanical barrier characteristics of this experimental polymeric agent, we concur with this reasonable explanation of the potential mechanism of action and encourage its use and study in the prevention of pericardial adhesions.

Disclosures and freedom of investigation

The polymeric matrix (Adhibit) was provided to the investigative team at each participating clinical center free of charge. All study-related costs associated with patient recruitment and post-surgical follow-up monitoring were reimbursed by the sponsor, Cohesion Technologies (Palo Alto, CA). The clinical investigators have no further financial relationship with the sponsor. Doctor Block is an independent clinical trials consultant, and was remunerated by the sponsor for work involved in data interpretation and preparation of this manuscript.

Acknowledgments

The statistical and data management support of Peter Shabe, MS, is greatly appreciated.

Footnotes

The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.

References

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4. Bailey L.L., Ze-jian L., Schulz E., Roost H., Yahiku P. A cause of right ventricular dysfunction after cardiac operations. J Thorac Cardiovasc Surg 1984;87:539-542.[Abstract]
5. Shapira N., Gordon C.I., Lemole G.M. Occlusion of aortocoronary vein grafts in association with bovine pericardium. Am J Cardiovasc Pathol 1990;3:87-90.[Medline]
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8. Hill A., Estridge T.D., Maroney M., et al. Treatment of suture line bleeding with a novel synthetic surgical sealant in a canine iliac PTFE graft model. J Biomed Mater Res 2001;58:308-312.[Medline]
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