Ann Thorac Surg 1997;63:1091-1094
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Effect of Physical Protection on the Mesothelial Integrity of the Pericardium
Aquilino Hurlé, MD,
María de la Vega, MD,
Juan J. Feijóo, MD,
Victor G. Ray, MD,
Cipriano Abad, MD,
Gerardo Ponce, MD,
José L. Pérez-Arellano, MD
Departments of Cardiovascular Surgery and Pathology, Hospital N. S. del Pino, Las Palmas de Gran Canaria, Canary Islands, Spain
Accepted for publication November 4, 1996.
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Abstract
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Background. Mesothelial integrity is essential for the prevention of pericardial adhesions. This study was performed to determine the effect of physical protection of the pericardium on mesothelial integrity.
Methods. A pericardial biopsy specimen was obtained at the time of pericardiotomy (0 minutes) in 10 patients undergoing a cardiac operation for the first time. The left free edge of the pericardiotomy was plicated inward to protect the mesothelium. Biopsy specimens were obtained from the protected and unprotected pericardium at 45 and 90 minutes after the start of extracorporeal circulation. Mesothelial integrity and the local inflammatory response were then assessed and graded histologically.
Results. The mesothelium was found to be present in the protected specimens at 0, 45, and 90 minutes, but it was found to be denuded in the unprotected specimens (p = 0.003 at 45 minutes; p = 0.004 at 90 minutes). Local inflammation was totally established in both the protected and unprotected specimens at 45 minutes.
Conclusions. Physical agents appear to be the main factor that is damaging to the pericardial mesothelium, and this is an important concept to be taken into consideration when designing a method to prevent pericardial adhesions.
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Introduction
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The formation of pericardial adhesions after open heart operations is a well-described sequela that can pose a major problem at reoperation. The reason for this is that they can cause the operative time to be prolonged and the risk of damage to the heart and other mediastinal structures at resternotomy to be increased [1]. There is also evidence that adhesions have a deleterious effect on cardiac function [2] and may lead to a reduction in aortocoronary graft patency [3, 4].
Factors such as the deposition of fibrin in areas of damaged mesothelium or the loss of pericardial fibrinolytic activity have been reported to play an important role in the pathogenesis of such adhesions [5, 6]. Cardiopulmonary bypass also seems to foster adhesion formation, as evidenced by some experimental studies [7]. A further cause known to trigger the formation of adhesions is physical trauma to the pericardium, and most experimental animal models of surgical pericarditis involve the traumatizing of the pericardium in a controlled manner. Methods used to injure the pericardium include mechanical damage inflicted with surgical swabs and instruments, desiccation, cold, stretching, blood spilling, and others, though it has not been determined which is the most traumatizing one. In any case, it appears that the preservation of mesothelial integrity can help prevent adhesions and this study was therefore performed to assess how physical protection of the pericardium affects the maintenance of mesothelial integrity.
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Material and Methods
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A total of 10 randomly chosen and consenting patients (9 male, 1 female; mean age, 60.0 ± 10.3 years; range, 43 to 78 years) without a medical history of immunologic disorders or of treatment with immunosuppressant drugs were included in the study. All were scheduled to undergo first-time open heart procedures with extracorporeal circulation (aortocoronary bypass in 8 patients and aortic valve replacement in the remaining 2). In all patients, the heart was approached by a median sternotomy and a longitudinal pericardiotomy. As soon as the pericardium was opened, a biopsy specimen of the pericardium was obtained (control at 0 minutes). Both sides of the pericardiotomy were suspended from the wound edge with silk stay sutures to create a pericardial well. The free pericardial edge on the left side of the pericardiotomy was then plicated inward with 4-0 monofilament interrupted sutures in such a way that the mesothelial layer was kept inside a pericardial "tunnel" and thus protected against physical agents. At 45 and 90 minutes after the start of extracorporeal circulation, biopsy specimens were taken from this protected side as well as from the right, unprotected side of the pericardium.
All biopsy specimens were processed in the same manner. As soon as they were obtained, they were fixed in a 10% formaldehyde solution and then embedded in paraffin. The histologic sections were stained with hematoxylin-eosin and assessed by the same histopathologist in a single blind manner. The grading system, proposed by Nkere and associates [5] was employed to quantify the degree of mesothelial damage and the severity of the local acute inflammatory response. Mesothelial was graded as follows: grade I, normal mesothelium; grade II, mesothelial integrity but with the presence of cuboidal mesothelial cells; grade III, a total absence of mesothelium (Fig 1
). Local inflammation was graded as follows: grade I, absence of inflammation; grade II, vascular congestion; grade III, margination of neutrophils; and grade IV, frank inflammation with neutrophils in the connective tissue.
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Fig 1. . Grades of mesothelial damage. (A) Pericardium showing normal flat mesothelial cells (grade I). (B) Mesothelial integrity but with the presence of cuboidal mesothelial cells (grade II). (C) Absence of mesothelium (grade III). (Hematoxylin and eosin; x200 before 35% reduction).
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The data were statistically analyzed using an overall Kruskal-Wallis test followed by an individual Kolmogorov-Smirnov test or Wilcoxon test when appropriate. The effect of the time of exposure was assessed by a paired Wilcoxon test. A p value of less than 0.05 was considered significant.
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Results
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The grading of the mesothelial damage and local inflammatory response in protected and unprotected pericardial specimens at 0, 45, and 90 minutes is summarized in Table 1.
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Mesothelial Damage
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No significant differences in mesothelial damage in protected specimens were found in relation to the time of sampling. However, when the mesothelial damage in unprotected specimens was compared for the different time points, significant differences were found between 0 and 45 minutes (p = 0.013) and between 0 and 90 minutes (p = 0.022) but no significant differences were found between 45 and 90 minutes. Moreover, significant differences between protected and unprotected specimens were noted at 45 minutes (p = 0.003) and at 90 minutes (p = 0.004).
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Local Inflammation
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There were early signs of inflammation at 0 minutes in 7 of 10 patients, and both protected and unprotected specimens showed a significative increase in the degree of inflammation at 45 minutes (p = 0.022) and at 90 minutes (p = 0.013), as compared with their status at 0 minutes. No significant differences were found between protected and unprotected specimens.
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Comment
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The formation of pericardial adhesions is a well-described phenomenon and is known to occur in all patients after open heart surgical procedures. It is important to prevent such adhesions because the risk of damage to the heart or other mediastinal structures at reoperations is then significantly raised [1].
Different methods of preventing adhesion formation, such as pericardial meshing [8], dextran pericardial washouts [9], and the use of pericardial substitutes [10, 11] or pharmacologic agents [12], have proved to be successful in experimental studies but disappointing clinically. In fact, the use of some pericardial substitutes, such as bovine pericardium, has been reported to lead to an increase in the amount and density of adhesions [13, 14]. Another method, primary closure of the pericardium, appears to confer some protection on the heart and great vessels [15] but does not prevent the formation of adhesions.
In most studies, these methods of prevention have been devised on empirical grounds, as shown by the fact that little attention has been paid to the physiopathologic basis of pericardial adhesions. Although the literature on this topic is sparse, it appears that the maintenance of the mesothelial integrity plays an important role in the prevention of adhesion formation, because, when the mesothelial layer is denuded, the basal lamina and the underlying connective tissue are exposed, allowing the deposition of large amounts of fibrin, which may then undergo organization by fibrosis [6]. Furthermore, the fibrinolytic activity exhibited by mesothelial cells [16] inhibits the formation of fibrin strands, which may be the precursors of adhesions [6].
Surgical trauma produces morphologic and functional changes in mesothelial cells. Specifically, the damaged mesothelial cell changes from being flat to cuboidal as the result of the redistribution of intracellular actin filaments [6]. Trauma also causes the mesothelial fibrinoytic activity to be reduced [17], particularly when cardiopulmonary bypass is used [5].
This study was conducted to determine the relative influences of the local inflammatory reaction and the local physical factors on the maintenance of mesothelial integrity during cardiopulmonary bypass.
In agreement with Nkere and associates [6], we observed that mild pericardial inflammation and mesothelial morphologic changes were already present at very early stages in the operation. After 45 minutes of extracorporeal circulation, margination of neutrophils was present in 40% of the patients and frank inflammation was present in the remaining 60%. At 90 minutes, however, the acute inflammatory response was completely established in all 10 patients. There were also no significant differences in the inflammatory response between the protected and unprotected side of the pericardium at 45 and 90 minutes. On the other hand, the mesothelial layer was present in all protected specimens at 45 minutes and in nine of ten protected specimens at 90 minutes, whereas it was completely denuded in the unprotected specimens after 45 minutes of extracorporeal circulation.
Our results demonstrate that physical trauma is the main cause of mesothelial destruction during cardiac operations with extracorporeal circulation and also that local inflammatory changes do not correlate with the degree of mesothelial damage. However, there is some experimental evidence that the systemic administration of methylprednisolone can prevent the formation of pericardial adhesions [12]. These authors also reported that the systemic administration of a nonsteroidal antiinflammatory drug, such as ibuprofen, does not prevent the formation of pericardial adhesions. In light of these data and our results, we believe that the prevention of serosal adherences achieved with steroids is based more on the known capacity of these drugs to impair healing rather than on a supposed mesothelial cytoprotective effect, which to our knowledge, has never been reported. If the former were the case, the administration of steroids, rather than preventing adhesions, could even be dangerous.
Because the maintenance of mesothelial integrity appears to be essential to the prevention of pericardial adhesions, we therefore conclude that the physical protection of the mesothelial layer should be considered during the design of methods to modify adhesion formation. Along these lines, Mitchell and colleagues [18] have reported their successful treatment of dogs in which they applied a coating of hyaluronic acid solution on the pericardium, a very slippery substance that appears to confer some mechanical protection on the mesothelial cells. However, again, this was an experimental study and the merits of this method must still be proved on clinical grounds. Padding of the pericardium during operation could be another protective method, but because this has not been subjected to even experimental study, its merits are only speculative at this time.
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Acknowledgments
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We are most grateful to Professor David J. Wheatley and to Mr Philip Belcher (Senior Lecturer), from the University Department of Cardiac Surgery at the Glasgow Royal Infirmary, Great Britain, for their critical review of the manuscript.
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Footnotes
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Address reprint requests to Dr Hurlé, Servicio de Cirugía Cardiaca, Hospital General de Alicante, C/ Maestro Alonso 109, E-03010 Alicante, Spain (e-mail: aquilino{at}redestb.es).
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Abstract
Introduction
