Introduction

Post pericardiotomy syndrome (PPS) was first described in 1953 in patients who developed fever and pleuritic pain after undergoing mitral valve surgery¹. Patients often present with PPS several days post-surgery; however, clinical symptoms may occur as late as several weeks to months after surgery and may be associated with significant morbidity^{2, 3}. It is believed that PPS results from a heightened immune response to injury following cardiothoracic surgery^{2, 3}.

Clinical Findings

Figure 1. MRI findings in postpericardiotomy syndrome. MRI images from a 55 year old male who developed postpericardiotomy syndrome after mitral valve repair. Panel A shows a SSFP cine image. Prominent visceral pericardium is seen (large white arrow) and is surrounded by a small pericardial effusion. There is also a small right pleural effusion (smaller white arrow at the bottom). Panel B is a delayed enhancement image obtained after injection of gadolinium. There is circumferential increase in the signal in the pericardial layer (white arrow) which indicates inflammation of the pericardium.

Clinical findings commonly seen in PPS include fever without an explainable cause beyond the first postoperative week, pericardial friction rub, pleuritic chest pain, new or worsening pleural effusion and new or worsening pericardial effusion (Figure 1). Based on two recent clinical trials (COPPS and COPPS-2) examining the therapeutic benefit of colchicine in PPS, a consensus has emerged in the diagnostic criteria for PPS. A diagnosis of PPS can be made if patients present with at least 2 of the above-mentioned 5 clinical findings^{4, 5}. Based on these criteria, the incidence of PPS varies between 9% to as high as 50% depending on the populations studied^2-9.

Medical Therapy for Prevention and Treatment of PPS

Steroids, nonsteroidal antiinflammatory agents, and colchicine have been used for the treatment of PPS. Success with steroids for treatment of PPS is limited; in a randomized control trial among pediatric patients undergoing cardiopulmonary bypass, there was no benefit of intravenous methylprednisolone in preventing PPS¹⁰. NSAIDS have been shown to be useful for treatment of PPS. A study of 1019 adult patients who underwent cardiac surgery showed that 600mg of ibuprofen taken 4 times daily or 25mg of indomethacin taken 4 times daily for 10 days was effective in reducing the incidence of PPS; however, a retrospective study of 177 pediatric patients who had undergone atrial septal defect closure found that aspirin did not reduce the incidence of PPS^{7, 11}. The use of colchicine for prevention of PPS has been tested in 2 large randomized control trials. In the COPPS trial, 360 consecutive patients undergoing cardiothoracic surgery were randomized to receive either placebo or colchicine (1.0-0.5mg twice daily on the first day followed by 0.5mg-0.25mg twice daily based on body weight) from the third postoperative day for 1 month. Colchicine significantly reduced the incidence of PPS compared with placebo (8.9% vs 21.1%, p = .002). Colchicine also reduced the incidence of postoperative pericardial effusions by 43.9% and pleural effusions by 52.3%. The incidence of adverse effects was similar between both colchicine and placebo. In COPPS-2, patients were pretreated with colchicine 48 to 72 hours before cardiac surgery. Although, the incidence of PPS was reduced and colchicine was especially effective among patients with elevated levels of C-reactive protein, there was a 2-fold increase of adverse effects and discontinuation of colchicine. This suggests that colchicine pretreatment may need to be used judiciously and only in those patients who might be at a high risk of developing PPS. This also highlights the need for developing diagnostic tests to accurately identify those patients who have the highest risk of developing PPS.

Risk Factors for PPS

The earliest epidemiologic study aimed at identifying those at risk of PPS included 994 patients who underwent cardiothoracic surgery at Johns Hopkins between November of 1984-1985¹². The incidence of PPS was 19% and patients who were younger were more likely to develop PPS compared to older individuals. Patients with previous pericarditis or treatment with prednisone were also associated with an increased odds of developing PPS. In a study of 688 Finnish patients who underwent CABG, blood transfusion was described as being strongly associated with PPS and diabetes was associated with a reduced risk of developing PPS; however, serologic markers such as hsCRP and WSR were not included in the multivariable model. The association between the levels of circulating cytokines and incidence of PPS has been evaluated in 75 patients who underwent coronary artery bypass grafting (CABG)¹³. A low preoperative IL-8 level was identified as a high risk marker for development of PPS. It is thought that IL8 may have a protective effect on endothelial and mesothelial cells and therefore patients with high preoperative levels of IL-8 may be less prone to PPS. The limited number of studies that have evaluated serum biomarkers and histologic markers that are unique to individuals who suffer PPS points to the need for a more systematic examination of the risk factors at the cellular and genomic level which confer an increased susceptibility to PPS.

Conclusion

PPS is an inflammatory response to cardiothoracic surgery and is often characterized by a new pericardial effusion and fever. Timely treatment with colchicine in combination with NSAIDS may be useful in treating PPS. There are few studies which have unequivocally defined the risk factors that predispose to PPS. There is a need for the identification of biomarkers that will allow targeted treatment of patients who are at high risk for developing PPS during the postoperative period.

References

1. Janton OH, Golver RP, O'Neill TJ, Gregory JE, Froid GF. Results of the surgical treatment for mitral stenosis: analysis of 100 cases. Circulation 1952; 6:321–333.
2. Imazio M, Hoit BD. Post-cardiac injury syndromes: an emerging cause of pericardial diseases. Int J Cardiol. 2013;168:648-652.
3. Imazio M, Brucato A, Rovere ME, Gandino A, Cemin R, Ferrua S, et al. Contemporary features, risk factors, and prognosis of the postpericardiotomy syndrome. Am J Cardiol. 2011;108:1183-7.
4. Imazio M, Trinchero R, Brucato A, Ferrazzi P, Rovere ME, Gandino A, et al., COPPS Investigators. Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J 2010;31:2749–2754.
5. Imazio M, Brucato A, Ferrazzi P, Pullara A, Adler Y, Barosi A, et al. Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation: the COPPS-2 randomized clinical trial. JAMA. 2014;312: 1016-23.
6. Clapp SK, Garson A Jr, Gutgesell HP, Cooley DA, McNamara DG. Postoperative pericardial effusion and its relation to postpericardiotomy syndrome. Pediatrics. 1980;66:585-8.
7. Horneffer PJ, Miller RH, Pearson TA, Rykiel MF, Reitz BA, Gardner TJ. The effective treatment of postpericardiotomy syndrome after cardiac operations: a randomized placebo-controlled trial. J Thorac Cardiovasc Surg. 1990;100(2):292-296.
8. Lehto J, Gunn J, Karjalainen P, Airaksinen J, Kiviniemi T. Incidence and risk factors of postypericardiotomy syndrome requiring medical attention: The finland postpericardiotomy syndrome study. J Thorac Cardiovasc Surg. 2015;15:51-53.
9. Finkelstein Y, Shemesh J, Mahlab K, Abramov D, Bar-El Y, Sagie A, et al. Colchicine for the prevention of postpericardiotomy syndrome. Herz 2002;27:791–794.
10. Mott AR, Fraser CD Jr, Kusnoor AV, et al. The effect of short-term prophylactic methylprednisolone on the incidence and severity of postpericardiotomy syndrome in children undergoing cardiac surgery with cardiopulmonary bypass. J Am Coll Cardiol 2001;37:1700–1706.
11. Gill PJ, Forbes K, Coe JY. The effect of short-term prophylactic acetylsalicylic acid on the incidence of postpericardiotomy syndrome after surgical closure of atrial septal defects. Pediatr Cardiol 2009;30:1061–1067.
12. Miller RH, Horneffer PJ, Gardner TJ, Rykiel MF, Pearson TA. The epidemiology of the postpericardiotomy syndrome: A common complication of cardiac surgery. Am Heart J 1988;116:1323-1329.
13. Jaworska-Wilczynska M, Magalska A, Piwocka K, Szymanski P, Kusmierczyk M Waski M et al. Low Interleukin-8 level predicts the occurrence of the post pericardiotomy syndrome. PLOS One 2014;9(10):1-8.

Keywords: Adult, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Biomarkers, Blood Transfusion, Body Weight, C-Reactive Protein, Cardiac Surgical Procedures, Cardiopulmonary Bypass, Chest Pain, Colchicine, Consensus, Coronary Artery Bypass, Cytokines, Diabetes Mellitus, Diagnostic Tests, Routine, Epidemiologic Studies, Friction, Gadolinium, Genomics, Heart Septal Defects, Atrial, Humans, Ibuprofen, Incidence, Indomethacin, Inflammation, Interleukin-8, Male, Methylprednisolone, Mitral Valve, Pain, Pericardial Effusion, Pericardiectomy, Pericarditis, Pericardium, Pleural Effusion, Postpericardiotomy Syndrome, Prednisone, Retrospective Studies, Risk Factors

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