2008;16:309-312 Asian Cardiovasc Thorac AnnGoki Matsumura, Toshiharu Shin’oka, Yoshito Ikada, Takahiko Sakamoto and Hiromi Kurosawa

Novel Anti-Adhesive Pericardial Substitute for Multistage Cardiac Surgery

This information is current as of September 15, 2010

http://asianannals.ctsnetjournals.org/cgi/content/full/16/4/309World Wide Web at:

The online version of this article, along with updated information and services, is located on the

Surgery and affiliated journal of The Association of Thoracic and Cardiovascular Surgeons of Asia. is the official journal of The Asian Society for CardiovascularThe Asian Cardiovascular & Thoracic Annals

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from

INTRODUCTIONRecently a large number of patients with congenital heart defects have required repeat sternotomy because reoperations and staged surgical procedures are increasing. Repeat sternotomy and dissections carry a risk of further reoperation because mediastinal adhesion formation may result in iatrogenic injury of the heart, arteries, or veins. In addition, mediastinal adhesions make it diffi cult for surgeons to identify anatomical features, prolong the operating time for dissections, and increase blood transfusion requirements.1 Closure of the pericardium is one of the strategies to prevent these drawbacks. However, pericardial closure is usually impossible because it may cause cardiac tamponade or

late constriction after surgery. Moreover, in a 2nd or 3rd repeat sternotomy, there remains no pericardium available for chest closure. So far, various materials, such as silicone rubber, polyurethane, fascia lata, expanded polytetrafl uoroethylene (ePTFE), heterologous porcine, equine, or bovine pericardium, Dacron, and dura mater have been employed as pericardial substitutes to secure safer resternotomy.2–11 The widely used ePTFE sheet is reported to be safe and effective in preventing cardiac injury at resternotomy.4,5 However, such nonabsorbable material might cause dense adhesions and severe inflammatory reactions including fibrotic change, calcifi cation, and mediastinitis after implantation.6,7,11 An ideal pericardial substitute to prevent these drawbacks

ORIGINAL CONTRIBUTION

Novel Anti-Adhesive Pericardial Substitute for Multistage Cardiac SurgeryGoki Matsumura, MD, Toshiharu Shin’oka, MD, Yoshito Ikada, PhD1, Takahiko Sakamoto, MD, Hiromi Kurosawa, MD

Department of Cardiovascular SurgeryThe Heart Institute of JapanTokyo Women’s Medical UniversityTokyo1Department of Medicine, Nara Medical UniversityNara, Japan

For reprint information contact:Goki Matsumura, MD Tel: 81 3 3353 8111 Fax: 81 3 3356 0441 Email: smatumur@hij.twmu.ac.jpCardiovascular Surgery, The Heart Institute of Japan, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku,Tokyo 162-8666, Japan.

ABSTRACTDense adhesions in the retrosternal space make reoperations diffi cult in the fi eld of cardiovascular surgery. Several substitutes for pericardium have been employed to prevent dense adhesions forming, but they have been unsatisfactory because of peel formation, calcifi cation, and infection. To overcome these drawbacks, a novel biodegradable pericardial substitute was developed from gelatin obtained from specifi c-pathogen-free porcine skin and a bioabsorbable polyester mesh, which persists while the adhesion reaction occurs in the retrosternal space. A clinical pilot study of this gelatin sheet was carried out in patients scheduled to receive multistage cardiac surgery. From February 2003 to July 2004, the material was used in 5 patients aged 0.4 to 3.0 years. There were no complications related to the gelatin sheet. The effectiveness of the material was evaluated when the sternum was reopened 1.4 ± 0.5 years later. It took 24.5 ± 6.0 min for the resternotomy, and all surgeons who participated in the surgery rated the effectiveness of the gelatin sheet as “good”. This anti-adhesive sheet prevented dense adhesions, suggesting that this material may be useful as a pericardial substitute for multistage pediatric cardiac surgery.

(Asian Cardiovasc Thorac Ann 2008;16:309–12)

2008, VOL. 16, NO. 4 309 ASIAN CARDIOVASCULAR & THORACIC ANNALS

70162.indd 309 7/15/2008, 6:26:12 PM

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from

ASIAN CARDIOVASCULAR & THORACIC ANNALS 310 2008, VOL. 16, NO. 4

Anti-Adhesive Pericardial Substitute Matsumura

repeat thoracotomy due to the gelatin material. The mean white blood cell counts on postoperative day 1,2 and 3 were 15,718 ± 6,796, 15,482 ± 3,890, and 14,990 ± 5,410 cells per microliter, respectively. The mean C-reactive protein levels on postoperative day 1, 2, and 3 were 4.3 ± 1.0, 5.4 ± 5.0, and 1.3 ± 1.4 mg·L-1, respectively. White blood cell counts normalized within 7 to 16 days in these patients. The resternotomy took 19 to 34 min (mean, 24.5 ± 6.0 min) from the start of the operation to sternal reopening (Table 2). In each case, the resternotomy was easily performed. All surgeons who participated in the operation scored the anti-adhesive effectiveness as “good”. The impression of adhesiveness in the site where the gelatin sheet was used and at other sites in the mediastinum, the time from the onset of the operation until the sternum was reopened, and the time from sternal reopening to the institution of cardiopulmonary bypass are listed in Table 2. Photographs of case no. 5 are shown in Figure 2. The anti-adhesion gelatin sheet was laid on the surface of the heart and vessels when this patient had a bidirectional

in reoperations is required, especially in the fi eld of pediatric cardiac surgery where multistage operations are often needed. As previous animal experiments revealed a cross-linked gelatin had anti-adhesion effects, we decided to move forward to a clinical pilot study.13–15

PATIENTS AND METHODSIn a non-controlled clinical study, 5 patients who were expected to require further repair of congenital defects received the anti-adhesive sheet between February 2003 and July 2004. There were 3 boys and 2 girls, ranging in age from 0.4 to 3.0 years (mean age, 1.5 ± 1.0 years). The main diagnosis and surgical procedures when the sheet was applied and when the sternum was reopened are shown in Table 1. The Tokyo Women’s Medical University Institutional Review Board approved the protocol. All of the patients’ families were informed and consented to the use of the material. The anti-adhesive effects of the substitute were evaluated by 3 surgeons who participated in the surgery, and scored as follows: 4, excellent (without adhesion); 3, good (slightly adhesive); 2, fair (quite adhesive); and 1, poor (densely adhesive).

An aqueous solution of gelatin derived from porcine skin was cast on a glass plate where a bioabsorbable polyglycolide mesh was laid, and allowed to dry in air, yielding a sheet of 0.2 mm in thickness. After cross-linking, the sheet was cut into 6 × 9 cm2 sections and sterilized with ethylene oxide gas. Prior to use as a pericardial substitute, the sheet was immersed in physiological saline for a few minutes, and fi xed in the mediastinum with surgical sutures. The gelatin sheet is shown in Figure 1.

RESULTSThe sternum was reopened 1.4 ± 0.5 years after the sheet had been placed (Table 1). There was no mortality or morbidity such as prolonged infl ammatory response, infectious complication, signs of tamponade, or early

Table 1. Profi le of 5 Cases of Resternotomy after Insertion of a Gelatin Sheet

Case Main Initial Time (years) No. Diagnosis Operation Reoperation to Resternotomy 1 ccTGA SP shunt Conventional Rastelli 0.92 TAC Redo Rastelli Konno, redo Rastelli 1.73 Single RV BDG shunt TCPC (lateral tunnel) 1.44 ccTGA Redo SP shunt Double switch operation 2.25 SRV BDG, redo PAB TCPC (external conduit) 0.8

BDG = bidirectional Glenn, ccTGA = congenitally corrected transposition of the great arteries, PAB = pulmonary artery banding, RV = right ventricle, SP = systemic-to-pulmonary, TAC = truncus arteriosus communis, TCPC = total cavopulmonary connection.

Figure 1. The anti-adhesion gelatin sheet after immersion in physiological saline. The sheet is translucent, fl exible, and durable, and supports a surgical suture.

70162.indd 310 7/15/2008, 6:26:15 PM

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from

Matsumura Anti-Adhesive Pericardial Substitute

2008, VOL. 16, NO. 4 311 ASIAN CARDIOVASCULAR & THORACIC ANNALS

Glenn shunt and repeat pulmonary artery banding (Figure 2A). When the patient had a repeat sternotomy 0.8 years later, there was no gelatin sheet left on the heart, and dense adhesions were not observed where the sheet had been applied (Figure 2B). However, dense adhesions were found between the inferior wall of the right ventricle and the diaphragm which had not been covered by the anti-adhesive sheet. It took approximately 19 min from the skin incision to resternotomy in this case, and it was 179 min before cardiopulmonary bypass was started (Table 2).

DISCUSSIONThe diffi culty due to adhesions in reoperations is well known. The presence of retrosternal adhesions prolongs reentry during cardiac surgery and carries a risk of direct myocardial injury and catastrophic hemorrhage.16 The pathogenesis of these adhesions is related to serosal denudation in association with intrapericardial blood.17

Unfortunately, early correction of congenital heart defects incurs a high probability of repeat surgery.4 Moreover, certain complex defects necessitate multistage repair, with one or more repeated thoracotomies. In reoperations requiring resternotomy, pericardial and mediastinal adhesions can obscure important anatomic structures, causing catastrophic bleeding and considerable morbidity

and mortality.12,18,19 Therefore, a pericardial substitute that avoids damage to the heart and great vessels should be employed between the sternum and the heart. However, several commonly used pericardial substitutes have been less than satisfactory. This fact prompted the development of a more favorable substitute for pericardium.

Our new anti-adhesive gelatin sheet fabricated from heterologous protein is designed to exist in the pericardial cavity during the infl ammatory and adhesion responses after surgery, followed by degradation and absorption with time. As great effectiveness of a gelatin sheet in preventing adhesions was reported in an animal model, we modifi ed the material utilizing bioabsorbable polyester mesh to reinforce the gelatin and provide suture stability.15 The gelatin degrades by enzymatic digestion and the mesh degrades by non-enzymatic hydrosis, so all foreign material remains in the pericardial cavity for a limited period after surgery. The advantages of a gelatin sheet reinforced with polyglycolic mesh might be expected to include reduced incidence of the drawbacks of the other pericardial substitutes commonly used in cardiac surgery. For safe application, we used gelatin derived from porcine skin to avoid unwanted infection such as bovine spongiform encephalopathy.15

Table 2. Effect of the Gelatin Sheet on Adhesions and Operative Times

Case Adhesions at Resternotomy Time (min) No. Gelatin Sheet Other Mediastinal Sites Start–Sternotomy Sternotomy–Bypass1 Slight Severe 20 2612 Slight Severe 34 1963 Slight Moderate 26 2654 Slight Severe 24 1765 Slight Moderate 19 160

Figure 2. Photographs of the operation in case no. 5. (A) The anti-adhesion gelatin sheet laid on the surface of the heart. (B) The surface of the heart when the sternum was reopened 0.84 years after the sheet had been applied.

70162.indd 311 7/15/2008, 6:26:17 PM

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from

ASIAN CARDIOVASCULAR & THORACIC ANNALS 312 2008, VOL. 16, NO. 4

Anti-Adhesive Pericardial Substitute Matsumura

Recently, a number of experimental studies on biodegradable materials as pericardial substitutes have been reported. Gabbay and colleagues20 demonstrated the feasibility of a biodegradable polyglycolic acid mesh that is rapidly absorbed and forms a thin layer of host collagen. They also reported the infl uence of cardiopulmonary bypass on the formation of adhesions in the retrosternal space. Absorbable materials are useful as they do not remain in vivo for a long time, and have less potential to form adhesions. We found the gelatin sheet to be effective as a pericardial substitute to prevent the formation of dense adhesions in the retrosternal space. However, we were not completely satisfi ed with the results because the only part covered by the sheet was between the retrosternal space and the right ventricle, and most of the heart and vessels that need to be dissected in further surgery were not covered. Nevertheless, we are convinced that utilizing the gelatin sheet can shorten the time for repeat sternotomy and dissection compared to the ePTFE sheet as a pericardial substitute (data not shown).

In congenital heart surgery, which often requires multistage operations, it is very important to dissect the anatomical structures easily and without any complication to conduct the next operation as safely and as quickly as possible. Therefore, we speculate that greater effi cacy of the sheet would be achieved when it can cover the whole area of the heart and vessels that might be dissected in further operations. This improved effi cacy would decrease the incidence of several risks in reoperations, lessen the incidence of blood transfusion, and shorten the operating time. These merits would benefi t patients who require multistage surgery and also the surgeons who have to carry them out. In this study, postoperative blood tests showed prolonged high white blood cell counts. We could not conclude whether or not these effects were related to the gelatin sheet. Further studies with a larger number of patients is required. We included only 5 patients in this pilot study. To verify the effi cacy of the gelatin sheet, a case-matched randomized controlled study should be performed in the future.

It was concluded that this novel anti-adhesive gelatin sheet prevented dense adhesions after sternotomy in humans, suggesting its effectiveness. This gelatin sheet could become a pericardial substitute and also an anti-adhesive material to avoid dense adhesion of the heart and vessels in patients requiring multistage cardiac surgery.

REFERENCES1. Dobell AR, Jain AK. Catastrophic hemorrhage during redo

sternotomy. Ann Thorac Surg 1984;37:273–8.2. Laks H, Hammond G, Geha AS. Use of silicone rubber as a

pericardial substitute to facilitate reoperation in cardiac surgery. J Thorac Cardiovasc Surg 1981;82:88–92.

3. Kohanna FH, Adams PX, Cunningham JN Jr, Spencer FC. Use of autologous fascia lata as a pericardial substitute following open-heart surgery. J Thorac Cardiovasc Surg 1977;74:14–9.

4. Jacobs JP, Iyer RS, Weston JS, Amato JJ, Elliott MJ, de Leval MR, et al. Expanded PTFE membrane to prevent cardiac injury during resternotomy for congenital heart disease. Ann Thorac Surg 1996;62:1778–82.

5. Amato JJ, Cotroneo JV, Galdieri RJ, Alboliras E, Antillon J, Vogel RL. Experience with the polytetrafl uoroethylene surgical membrane for pericardial closure in operations for congenital cardiac defects. J Thorac Cardiovasc Surg 1989;97:929–34.

6. Chanda J, Kuribayashi R, Abe T. Use of the glutaraldehyde-chitosan-treated porcine pericardium as a pericardial substitute. Biomaterials 1996;17:1087–91.

7. Gallo JI, Artiñano E, Duran CM. Clinical experience with glutaraldehyde-preserved heterologous pericardium for the closure of the pericardium after open heart surgery. Thorac Cardiovasc Surg 1982;30:306–9.

8. Mills SA. Complications associated with the use of heterologous bovine pericardium for pericardial closure. J Thorac Cardiovasc Surg 1986;92:446–9.

9. Skinner JR, Kim H, Toon RS, Kongtahworn C, Phillips SJ, Zeff RH. Infl ammatory epicardial reaction to processed bovine pericardium: case report. J Thorac Cardiovasc Surg 1984;88:789–91.

10. Mazuji MK, Lett JC. Siliconized Dacron as a pericardial patch. Arch Surg 1963;87:446–9.

11. Bonnabeau RC Jr, Armanious AW, Tarnay TJ. Partial replacement of pericardium with dura substitute. J Thorac Cardiovasc Surg 1973;66:196–201.

12. Ozeren M, Han U, Mavioglu I, Simsek E, Soyal MF, Guler G, et al. Consequences of PTFE membrane used for prevention of re-entry injuries in rheumatic valve disease. Cardiovasc Surg 2002;10:489–93.

13. Matsuda S, Se N, Iwata H, Ikada Y. Evaluation of the antiadhesion potential of UV cross-linked gelatin fi lms in a rat abdominal model. Biomaterials 2002;23:2901–8.

14. Sakuma K, Iguchi A, Ikada Y, Tabayashi K. Closure of the pericardium using synthetic bioabsorbable polymers. Ann Thorac Surg 2005;80:1835–40.

15. Yoshioka I, Saiki Y, Sakuma K, Iguchi A, Moriya T, Ikada Y, et al. Bioabsorbable gelatin sheets latticed with polyglycolic acid can eliminate pericardial adhesion. Ann Thorac Surg 2007;84:864–70.

16. DeLeon SY, LoCicero J 3rd, Ilbawi MN, Idriss FS. Repeat median sternotomy in pediatrics: experience in 164 consecutive cases. Ann Thorac Surg 1986;41:184–8.

17. Ryan GB, Grobéty J, Majno G. Postoperative peritoneal adhesions. A study of the mechanisms. Am J Pathol 1971;65:117–48.

18. Londe S, Sugg WL. The challenge of reoperation in cardiac surgery. Ann Thorac Surg 1974;17:157–62.

19. Loop FD. Catastrophic hemorrhage during sternal reentry. Ann Thorac Surg 1984;37:271–2.

20. Gabbay S, Guindy AM, Andrews JF, Amato JJ, Seaver P, Khan MY. New outlook on pericardial substitution after open heart operations. Ann Thorac Surg 1989;48:803–12.

70162.indd 312 7/15/2008, 6:26:24 PM

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from

2008;16:309-312 Asian Cardiovasc Thorac AnnGoki Matsumura, Toshiharu Shin’oka, Yoshito Ikada, Takahiko Sakamoto and Hiromi Kurosawa

Novel Anti-Adhesive Pericardial Substitute for Multistage Cardiac Surgery

This information is current as of September 15, 2010

& ServicesUpdated Information

http://asianannals.ctsnetjournals.org/cgi/content/full/16/4/309including high-resolution figures, can be found at:

References http://asianannals.ctsnetjournals.org/cgi/content/full/16/4/309#BIBL

This article cites 20 articles, 12 of which you can access for free at:

Permissions & Licensing info@asiapex.comshould be submitted via email to:

Requests to reproduce this article in parts (figures, tables) or in its entirety

Reprints info@asiapex.comFor ordering reprints, please email:

by on September 15, 2010 asianannals.ctsnetjournals.orgDownloaded from