Management of purulent pericarditis with intrapericardial fibrinolysis: a review

Purulent pericarditis remains a life-threatening pathology. There is no consensus on its medicosurgical management. Nevertheless, total pericardiectomy eradicates focus of infection and provides a better outcome than simple pericardial drainage. Because of high morbidity, intrapericardial fibrinolysis has been considered as a less invasive approach for prevention of persistent and constrictive pericarditis. Literature was reviewed using MEDLINE database. We evaluated the pathophysiological rationale, clinical efficacy, outcome, and complications of pericardial fibrinolysis. Experimental data demonstrate that fibrinoformation is observed in the first week after onset of the disease, and is an essential step in the evolution to constrictive pericarditis and chronic pericarditis. Seventy-five cases of fibrinolysis in purulent pericarditis have been analyzed. Among the 41 analyzable cases, only 2 treated by late fibrinolysis encountered failure requiring surgery. Only 1 serious complication was described. Despite the lack of definitive evidence, potential benefits of fibrinolysis outweigh its very low morbidity. Fibrinolysis is a promising and less invasive alternative to surgery in the management of purulent pericarditis. It should be applied as soon as possible with the aim to prevent both constrictive and purulent pericarditis. Nevertheless, in case of failure of fibrinolysis, total pericardiectomy remains an option allowing a complete eradication of infection. Introduction Purulent pericarditis (PP) was a common complication of pulmonary infection before the antibiotic era [1]. Despite medical progress, PP is still associated with high mortality attributed to early and late complications, chronic purulent pericarditis and constrictive pericarditis. These late complications may be prevented by early pericardiectomy known for its potential morbidity. Twenty years ago, intrapericardial fibrinolysis emerged as a promising and less invasive alternative to surgery. Nevertheless, there is no consensus about its indication in PP. History, pathophysiology, complications and surgical management of PP are briefly described. At the light of physiological and histological data, we reviewed the rationale of fibrinolysis in PP, the evidences of its efficacy, and all publications on indications, timing, results, and complications of this technique. Definitions and etiologic classification Purulent pericarditis is defined by a neutrophilic pericardial effusion infected by a bacterial, fungal, or parasitic agent. Tuberculous pericarditis are not PP but lymphocytic pericarditis, and will not be discussed. Classification of PP comprises 5 etiologic entities (Table 1) [1,2]. Purulent pericarditis arising from a pleuropulmonary infection was the main etiology in the early 20 th century, before the advent of antibiotics [1,3]. Oesophageal and cardiothoracic surgeries, immunosuppressive therapy and chemotherapy have made emerge new predisposing conditions [2]. Diagnosis When PP is suspected, the diagnosis is confirmed by pericardiocentesis guided by echocardiography yielding purulent fluid. It may have different clinical features according to the aetiology. In a context of pneumonia the diagnosis may be suspected when infection doesn’t respond adequately to antibiotic treatment. In this case, echocardiography or computed tomography scan of chest may disclose thoracic complications such as pleural empyema or pericardial effusion [4,5] (figure 1). Interestingly, PP may have an insidiously subtle presentation, and classical pericardial signs can be absent until tamponade [2,6]. Pain chest or pericardial friction rub are observed in about 50 % of cases [7]. These data are in agreement with autopsy series of Klacsmann showing that of 55 PP, only 10 had been discovered antemortem [1]. Indeed, before the advent of echocardiography, less than 20% of PP discovered at autopsy had been clinically suspected [1]. This poor index of suspicion results in underdiagnosis and late diagnosis at an advanced stage of the disease after onset of pericardial adhesions loculations [8]. Complications Purulent pericarditis may be accompanied by tamponade and septic shock, the 2 early life threatening complications which have no specificity in this setting. On the contrary, the 2 late complications constrictive pericarditis and persistent/chronic PP, imply specific considerations and management [1,2]. Constrictive pericarditis is defined by thickening and fusion of pericardium causing low pericardial compliance with symptoms of chronic right heart failure. It may cause hemodynamic compromise with low cardiac outpout because of adiastoly with impaired cardiac filling. Pericardial fibrosis is caused by chronic or subacute pericardial inflammation which is associated with fibroblast proliferation and collagen deposition. In the largest meta-analysis of PP by Gaudelus that specially addressed to constrictive pericarditis, there were 19 cases (3.5%) of constrictive pericarditis beyond 524 published PP [9]. This frightened complication is specifically expected when no pericardiectomy has been performed [9]. Persistent pericarditis is defined by a chronic or recurrent purulent pericardial effusion. Because chronic inflammation can cause fibrosis, persistent purulent pericarditis may be followed by constrictive pericarditis. Nevertheless, even if persistent and constrictive pericarditis may be associated, these entities have distinct clinical features. This late complication of PP is much more frequent than constrictive pericarditis but has rarely been classified as chronic purulent pericarditis. Therefore, its incidence cannot be precisely known. Many authors have well described adhesions, loculations of pericardial effusion, with persistence or recurrence of PP due to the presence of thick fibrin clots preventing complete evacuation of pus through pericardial drains [10-14]. In these cases, despite drainage and appropriate antibiotherapy PP, chronic purulent discharge persists several weeks until death due to septic shock or tamponade. At this stage, surgical management with pericardiectomy is challenging, with high morbidity because of pericardial adherences and impaired general status of patient. In fact, the real challenge should be to prevent chronic and constrictive pericarditis. Physiopathology of PP and of complications Few publications studied the physiological mechanisms of purulent pericarditis, but this pathology shares some pathophysiological similarities with empyema that has been widely studied. Clinical and experimental studies show that contiguous spread of lung infection causes pleural mesothelial barrier dysfunction |15]. First, activated mesothelial cells release vascular endothelial growth factor (VEGF) leading to exsudative pleural effusion with pleural inflammation by increasing protein vascular permeability. The second step is bacterial invasion of pleural space that enhances inflammatory response by attracting leucocytes. By expressing tissue factor, activated leucocytes activate platelets and coagulation, both resulting in fibrinoformation [16]. Fibrin deposits are responsible of pleural adhesion, thickening and loculation of effusion, therefore preventing easy drainage and antibiotics diffusion. When drainage is suboptimal, the pathologic process may relapse and progress. Finally, when the process continues, subacute or chronic inflammation leads to fibrosis due to collagen secretion by fibroblastic proliferation. An experimental model in sheep argued for a very close pathophysiological process of PP leading from pericardial inflammation to pericardial adhesions and fibrosis [17]. In addition of demonstrating histological course of PP, this study provides timings of occurrence of the essential steps of the disease. After a first inflammatory stage, fibrin strands appeared since the third day. At 6 days, newly formed collagen fibrils were deposited throughout the interstitial spaces and among the aggregated cells. At 2 weeks, intrapericardial fibrosis had produced focal adhesions between the pericardial surfaces. At 1 month, extensive areas of the pericardial cavity were obliterated [17]. Another experimental study showed comparable timings in histological progression [18]. These experimental data clearly explain how PP evolves to persistent and constrictive pericarditis. First, chronic/persistent purulent pericarditis is related to the absence of effective drainage because of loculation and pericardial adhesion [19,20]. Secondly, constrictive pericarditis is related to pericardial fibrosis which could be detected 2 weeks after the beginning of the pathological process [17,18]. Furthermore, these studies shows that whatever the aetiology, fibrinoformation is the essential step and a cornerstone in the pathogenesis of both persistent/chronic and constrictive pericarditis. Thus, fibrin may be a therapeutic target in the