Intrapericardial Triamcinolone Administration for Autoreactive Pericarditis

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  Request Is intrapericardial triamcinolone a safeand effective treatment option for autore-active pericarditis? Response BACKGROUND Pericarditis is responsible for chestpain in 1–5% of patients who present tothe emergency department with chest painwithout myocardial infarction (MI). 1,2 It isoften characterized by acute onset of ret-rosternal or left precordial chest pain that ispleuritic and radiating. Pericarditis-associ-ated chest pain is exacerbated by inspira-tion and supine positioning. 3,4 Patients mayalso experience a prodrome of fever,malaise, and myalgia. 3,5 Additional cardi-nal features of pericarditis include pericar-dial friction rub and widespread concaveST-segment elevation and PR-segment de-pression shown on electrocardiography. 1,4 The causes of acute pericarditis areextensive, although 90% of the cases areattributed to a viral or idiopathic etiolo-gy. 3-6 While infrequent, nonviral infec-tious causes include bacteria, fungus, ortuberculosis. Acute MI, aortic dissection,pericardial injury, trauma, neoplasms, uremia, autoimmunedisorders, metabolic syndromes, cardiac procedures, andradiation therapy have also been associated with pericardi-tis. Additionally, medications including dantrolene, dox-orubicin, hydralazine, isoniazid, mesalamine, procaina-mide, rifampin, penicillin, and phenytoin can contribute toacute pericarditis. 3,4 Acute pericarditis is generally self-limiting; however, itcan be complicated by tamponade, constriction, or recur-rence. 3 Approximately 24% of patients experience recur-rence after the initial episode, the majority of which is Intrapericardial Triamcinolone Administration for AutoreactivePericarditis Jorie A Glick Frasiolas and William D Cahoon Jr Drug Information Rounds Author information provided at end of text. The Annals of Pharmacotherapy  2010 October, Volume 44  1641 OBJECTIVE : To review published literature regarding the safety and effectivenessof intrapericardial triamcinolone for the treatment of autoreactive pericarditis. DATA SOURCES : Searches of MEDLINE (1966–June 2010) and CochraneDatabase (1993–June 2010) were conducted. Limits included articles publishedin English reporting on human subjects. Additional data were identified throughbibliographic reviews. STUDY SELECTION AND DATA EXTRACTION : All English-language articles identifiedfrom the data sources were evaluated. Trials, studies, and case reports wereeligible for inclusion if they evaluated the safety and/or efficacy of intrapericardialtriamcinolone for the management of autoreactive pericarditis. DATA SYNTHESIS : Systemic corticosteroids offer an effective treatment option forautoreactive pericarditis; however, their use is limited by adverse effects and theyare an independent risk factor for pericarditis recurrence. One case series and 3open-label trials evaluating intrapericardial triamcinolone for the management ofautoreactive pericarditis are reviewed. Included studies were limited by smallsample sizes (N = 2–84), lack of control groups, short durations of follow-up (24 hto 12 mo), use of adjuvant agents, omission of patient demographic data,subjective report of symptom relief, and lack of consistent dose of intrapericardialtriamcinolone. Despite these limitations, the data suggest symptom resolutionand reduced pericarditis recurrence with administration of intrapericardialtriamcinolone to patients with autoreactive pericarditis. CONCLUSIONS : There is growing evidence that intrapericardial triamcinolone issafe and effective for the management of autoreactive pericarditis. Theappropriate regimen (dose and duration of treatment), adverse effect profile, andspecific therapeutic role require further investigation. KEY WORDS : autoreactive pericarditis, corticosteroids, intrapericardial admini-stration, triamcinolone. Ann Pharmacother  2010;44:1641-6.Published Online, 24 Aug 2010,  ,DOI 10.1345/aph.1P294  at PENNSYLVANIA STATE UNIV on May 25, 2015aop.sagepub.comDownloaded from   thought to be autoreactive. 7-9 Autoreactive pericarditis is anautoimmune process in which antibodies are directedagainst myocardial tissue in the absence of viral or bacteri-al antigens. 3,10 The following criteria are required for a di-agnosis of autoreactive pericarditis: antibodies againstheart muscle tissue (antisarcolemmal) or >5.0 × 10 9  /L lym-phocytes and mononuclear cells in the pericardial fluid,signs of myocarditis on biopsy, and exclusion of otherknowncauses of pericarditis. 3,10 The mainstay of treatment for autoreactive pericarditis isnonsteroidal antiinflammatory drugs (NSAIDs) or aspirin.Goals of therapy include relieving chest pain, reducing in-flammation, and preventing complications. 1,3,4 NSAIDs are85–90% effective at eliminating chest pain; however, theyhave not been evaluated for preventing recurrence. 11-13 Inpatients who do not respond to NSAIDs or aspirin,colchicine in combination with NSAIDs has been shownto relieve symptoms (10% vs 31%, p = 0.03) and preventrecurrent pericarditis (24% vs 50.6%, p = 0.02) to a greaterdegree than aspirin alone. 14-17 The exact mechanism of colchicine’s benefit in pericarditis has not been fully eluci-dated, although it is thought to be related to its antiinflam-matory properties. Systemic corticosteroids are effective inpatients who have persistent symptoms despite therapywith NSAIDs and colchicine. Their use should, however,be limited because of the risk for significant adverse ef-fects. 10,18 Additionally, systemic corticosteroids have beenidentified as an independent risk factor for pericarditis re-currence. 17-19 Local delivery by intrapericardial administra-tionmay provide a method to deliver high-dose cortico-steroids while avoiding systemic adverse effects and recur-rence in patients with autoreactive pericarditis. Intrapericardial administration of steroids was first pro-posed in 1964 for tuberculous pericarditis 20 and then againin 1977 for the treatment of rheumatoid pericardial tam-ponade. 21 Subsequently,it has been used for the treatmentof uremic and dialysis-associated pericarditis. 3 More re-cently, it has been suggested as a treatment option for au-toreactive pericarditis. 10,22,23 Although several steroids havebeen evaluated for intrapericardial administration, triam-cinolone is the most commonly used in clinical practice.This review focuses on literature evaluating the safety andefficacy of intrapericardial triamcinolone in order to defineits role, if any, in the management of autoreactive peri-carditis. Literature Review Aliterature search using MEDLINE (1966–June 2010)and the Cochrane Database (1993–June 2010) was con-ducted for English-language articles using the search termsautoreactive pericarditis, pericardial disease, corticoste-roids, triamcinolone, and intrapericardial administration.Bibliographies of identified articles were subsequently re-viewed for additional citations. One case series 24 and 3open-label trials 10,22,23 have evaluated the safety and effica-cy of intrapericardial triamcinolone for autoreactive peri-carditis. The results of these trials and studies are summa-rized below and in Table 1. CASE SERIES Autoreactive pericarditis frequently occurs followingcardiac electrophysiologic (EP) procedures. 25 Maxwell etal. presented 3 patients who developed autoreactive peri-carditis following an EP procedure that was successfullytreated with intrapericardial triamcinolone. 24 The first was an81-year-old woman admitted for an elective pacemakerplacement who subsequently developed a pericardial effu-sion. She complained of midsternal chest pressure that wors-ened with inspiration. After failing a short course of standardtherapy with NSAIDs, colchicine, and opioids, she was pre-scribed intrapericardial triamcinolone 50 mg. Three hoursafter administration, her chest pain decreased from 10 on ascale of 0–10 to 0. The patient did experience significantsubsternal chest pain during triamcinolone administration;however, she had not been given prophylactic pain medica-tion. A second patient, a 68-year-old male with a history of recurrent atrial fibrillation, underwent radiofrequency abla-tion, which was complicated by tamponade. A pericardialeffusion was drained and the patient was started on intermit-tent opioids, followed by colchicine and NSAIDs, with littleimprovement in chest pain. He was subsequently given 1dose of intrapericardial triamcinolone 200 mg (2 mg/kg)over 24 hours. After triamcinolone administration, he re-mained asymptomatic and recurrence free. Finally, a 72-year-old man was admitted for radiofrequency ablation forrefractory atrial fibrillation, which was followed by pericar-dial tamponade. Triamcinolone 80 mg (1 mg/kg) was in-stilled intrapericardially.It is unknown whether this patientreceived any therapies for pericarditis prior to initiation of triamcinolone. Although the patient reported pain relief, hecontinued to require additional intravenous pain medica-tions. No adverse effects were reported.This case series presents the successful treatment of peri-carditis in 3 patients; however, it is unknown whether thesepatients met the criteria for autoreactive pericarditis. 24 Addi-tionally,while patients 1 and 2 received triamcinolone afterfailing only a brief course of standard therapy, it was not re-ported whether patient 3 received NSAIDs or colchicine.There was also significant variability in dosing regimen be-tween the cases reported. Additionally, because patients re-ceived other therapies, including NSAIDs, colchicine, andopioids, it cannot be determined whether the pain relief wasdue solely to triamcinolone. Although the authors reportedno episodes of recurrence, patients were followed at a sin-gle institution for only 6 months after presentation. Despitethe limitations to this case series, it does provide successful 1642   The Annals of Pharmacotherapy  2010 October, Volume  JAG Frasiolas and WDCahoon Jr  at PENNSYLVANIA STATE UNIV on May 25, 2015aop.sagepub.comDownloaded from   examples of intrapericardial steroid administration for au-toreactive pericarditis following EP procedures. OPEN-LABEL TRIALS Many of the data regarding intrapericardial triamcino-lone administration came from an open-label pilot studyconducted by Maisch et al. that evaluated the safety and ef-ficacy of intrapericardial treatment of inflammatory andneoplastic pericarditis. 22 Fourteen patients with autoreac-tive pericarditis, defined as a predominance of lympho-cytes in the pericardial fluid, presence of antimyolemmalantibodies, and exclusion of fungal and bacterial infection,who were undergoing pericardiocentesis and had at least12 months of follow-up data were included. Patients re-ceived triamcinolone 1 g intrapericardially over 24 hours.At 3 and 6 months, 1 (7%) and 2 (14%) patients developedrecurrence, respectively. The most commonly reported ad-verse effect was hyperglycemia. This pilot study found thattriamcinolone 1 g administered intrapericardially was ef-fective for preventing recurrence. 22 Reported recurrencerates with triamcinolone were similar to those reported instudies that evaluated standard therapy with colchicine. 11-17 This study represents the first trial that evaluated in-trapericardial triamcinolone for autoreactive pericarditis. 22 Although it provided initial data about the safety and effi-cacy of intrapericardial triamcinolone, it is limited by itsobservational design. One of the other limitations of thisstudy is that the investigators did not report whether patientsreceived standard therapies for treatment of pain or inflam-mation associated with pericarditis. Additionally, they did notspecify the dose or duration of therapy in patients with recur-rence that required additional treatment. Although 3 patientswere reported to have hyperglycemic episodes, the methodsfor monitoring adverse effects were not clear. It is unknownwhether patients were assessed for other systemic adverse ef-fects related to steroid administration. Despite these limita-tions, results of this trial do suggest that intrapericardial triam-cinolone 1 g may prevent recurrence of symptoms and peri-carditis without significant systemic toxicity.At the time the above trial was conducted, there was notechnology available to safely perform pericardiocentesisin patients with pericardial effusions smaller than 200 mL.Following the introduction of the PerDUCER device, in-vestigators from the previous trial were able to evaluate in-trapericardial triamcinolone in 2 patients with autoreactivepericarditis and minimal pericardial effusion. 23 Patientswere considered to have autoreactive pericarditis based onthe number of lymphocytes and mononuclear cells in thepericardial fluid, the presence of antibodies against hearttissue, and the exclusion of active viral or bacterial infec-tion or malignancy. After confirmatory diagnosis with en-domyocardial biopsy, both patients received intrapericardialtriamcinolone 300 mg/m 2 diluted in 100 mL of NaCl 0.9%  Intrapericardial Triamcinolone for Autoreactive Pericarditis The Annals of Pharmacotherapy  2010 October, Volume 44  1643 Table 1. Data Evaluating Intrapericardial Triamcinolone for Autoreactive Pericarditis Pts., Triamcinolone AdjuvantReference Design Diagnosis (n) Dose Therapy Efficacy Results Adverse Events MaxwellCase Autoreactive Patient 1: 50 mg Patient 1: Patients 1 and 2 reported pain relief within Patient 1: pain on(2010) 24 seriespericarditis followingPatient 2: 2 mg/kgmorphine iv,hours of administrationinstillationelectrophysiologicPatient 3: 1 mg/kgketorolac iv,Patient 3 reported pain relief, but continuedPatients 2 and 3:procedure (3)colchicineto require iv analgesianonePatient 2:No recurrence for any pt. at 6 mofentanyl iv,morphine iv,ibuprofen,colchicinePatient 3: NRMaisch OL, Autoreactive effusions1 g over 24 h NRAt 3 and 6 mo, 1 (7%) and 2 (14%) of 3 (21.4%) (1999) 22 pilotundergoingtriamcinolone pts. had recurrence,Nondiabetic pts.studypericardiocentesisrespectivelydeveloped hyper-(14)glycemiaMaisch OL, Autoreactive 300 mg/m 2 NRBoth pts. reported pain relief after instillationNR(2000) 23 pilotpericarditis withNeither pt. had recurrence of pericarditis atstudyminimal pericardial12 moeffusion (2)Maisch OL, Confirmed chronic600 mg/m 2 (54) Colchicine At 3 mo, 92.6% of high-dose and 86.7% ofMore high-dose (2002) 10 pilotautoreactiveor 300 mg/m 2 0.5 mg 3low-dose triamcinolone pts. were withoutpts. developedstudypericarditis (84)(30)times dailysymptoms or recurrence (p = 0.36)Cushing’s for 6 moAt 12 mo, 86% of high-dose pts. weresyndrome atsymptom- and recurrence-free vs 82.1%follow-up (29.6% of low-dose pts. (p = 0.63)vs 13.3%, p < 0.05)NR = not reported; OL = open-label.  at PENNSYLVANIA STATE UNIV on May 25, 2015aop.sagepub.comDownloaded from   (normal saline) over 24 hours. The first patient was a 26-year-old male who presented with flu-like symptoms andprecordial pain. Fourteen hours after instillation, the patientreported no pain. The second patient was a 59-year-oldwoman who complained of chest pain. She was found tohave a recurrence of her pericardial effusion, for which sheunderwent pericardiocentesis 6 months previously. The effu-sion was evacuated and the patient received intrapericardialtriamcinolone. Both patients experienced symptom relief andremained asymptomatic and without recurrence at 12-monthfollow-up. No adverse effects were reported. The authors concluded that a lower dosage of 300mg/m 2 may be considered for treating autoimmune peri-carditis in patients with minimal pericardial effusions;however, there were limitations to this study. 23 Like the ini-tial trial, these follow-up data are limited by the study’sob-servational design, lack of documentation, and small sam-ple size. Additionally, it was not reported whether patientsreceived standard therapy prior to initiation of intrapericar-dial triamcinolone. Finally, the investigators concluded thattriamcinolone was not associated with any adverse effects;however, the method for monitoring adverse effects wasnot clearly stated. Therefore, it cannot be concluded thatintrapericardial triamcinolone is effective or safe for au-toreactive pericarditis based solely on these data.The largest study to date that evaluated intrapericardialtriamcinolone for autoreactive pericarditis with pericardialeffusion was also conducted by Maisch et al. 10 The studycompared the safety and efficacy of low- versus high-doseintrapericardial triamcinolone. Eligible patients were diag-nosed with autoreactive pericarditis based on the followingcriteria: increased number of lymphocytes and mononuclearcells in the pericardial fluid; presence of antibodies againstheart muscle tissue; signs of myocarditis on biopsy; and ex-clusion of active viral infection, tuberculosis or other bacterialinfection, neoplasm, and systemic and metabolic disorders.No eligible patients were excluded. Eighty-four patients withconfirmed autoreactive pericarditis received triamcinolone600mg/m 2 (n = 54) or 300 mg/m 2 (n = 30) administered in-trapericardially over 24 hours. All patients were prescribedcolchicine as adjuvant therapy.The primary efficacy end-points were symptom improvement and pericarditis recur-rence. There was no statistically significant difference insymptomatic recurrence between the 2 groups, with bothgroups experiencing recurrence-free rates of greater than80%. Intrapericardial instillation of triamcinolone was not as-sociated with any acute adverse effects; however, patients inboth groups developed iatrogenic Cushing’s syndrome at fol-low-up, with those in the high-dose group experiencing agreater rate of Cushing’ssyndrome. The authors concluded that intrapericardial administra-tion of triamcinolone 300 mg/m 2 was as effective as 600mg/m 2 ,with fewer adverse effects. 10 The rates of symptomrelief and recurrence were similar with triamcinolone com-pared to those reported in studies of standard therapy withNSAIDs or colchicine. 11-17 While this trial added to the lit-erature evaluating the efficacy and safety of intrapericar-dial triamcinolone, it was limited by the lack of a controlgroup. Use of standard pericarditis therapy must be consid-ered when evaluating the treatment effect of triamcinolone.Both treatment groups received adjuvant colchicine therapy,while NSAID use was not reported. Therefore, it cannot bedetermined whether patients benefited from triamcinolone orcolchicine. Furthermore, the incidence of adverse effects wasnot well reported. Cushing’s syndrome, while less frequentwith the 300-mg/m 2 dose, still affected 13.3% of the low-dose group. This is concerning, as Cushing’s syndrome isassociated with significant morbidity and mortality in thefirst year after diagnosis. 26 The conclusion that can bedrawn from this study is that a lower dose of intrapericar-dial triamcinolone (300 mg/m 2 )provides similar treatmenteffect with a reduced incidence of Cushing’s syndrome ascompared with higher doses (600 mg/m 2 )of triamcinolone. Discussion Autoreactive pericarditis is characterized by pain and in-flammation that can be treated with NSAIDs or colchicine;however, patients may be resistant to these therapies. 1,3 In-trapericardial instillation of triamcinolone offers a methodfor administering glucocorticoids, while potentially mini-mizing adverse effects associated with systemic adminis-tration. 10,23,24 Based on current literature, intrapericardial tri-amcinolone may provide symptom resolution and preventpericarditis recurrence in autoreactive pericarditis. Thestudies and trials reviewed here were limited by hetero-geneity in study design, small sample size, lack of controlgroups, short duration of follow-up, use of adjuvant agents,omission of patient demographic data, subjective reports of symptom relief, and lack of consistent dose; therefore, re-sults from these studies should be interpreted cautiously.Based on the data currently available, the ideal dose of intrapericardial triamcinolone cannot be determined; how-ever, the largest trial to date supports the use of triam-cinolone 300 mg/m 2 administered over 24 hours. 10 Thecurrent literature is lacking in its assessment of both localand systemic adverse effects, although the most commonlyreported adverse effect appears to be pain on instillation. Inorder to minimize pain, patients should receive properanalgesia and triamcinolone should be diluted in at least100 mL of 37 ˚ C(warm) normal saline. In addition to painon administration, intrapericardial triamcinolone can causeinfection and/or the development of purulent pericarditis.Feinroth et al. described a case of uremic pericarditis treat-ed with intrapericardial triamcinolone that resulted in Staphylococcus aureus infection and purulent pericarditisrequiring pericardiectomy. 27 Additionally,asymptomaticiatrogenous arteriovenous fistula of the mammary artery 1644   The Annals of Pharmacotherapy  2010 October, Volume  JAG Frasiolas and WDCahoon Jr  at PENNSYLVANIA STATE UNIV on May 25, 2015aop.sagepub.comDownloaded from 
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