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A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion
IJCA-25558; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short communication
A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion Alison B. Wiyeh a,b,⁎, Eleanor A. Ochodo a, Charles S. Wiysonge b, Aloysious Kakia c, Abolade A. Awotedu d, Arsen Ristic e, Bongani M. Mayosi f a
Centre for Evidence-based Health Care, Department of Global Health, Stellenbosch University, Cape Town, South Africa Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa Department of Family Medicine and Rural Health, Walter Sisulu University, Mthatha, South Africa d Department of Medicine, Nelson Mandela Academic Hospital and Walter Sisulu University, Mthatha, South Africa e Department of Cardiology, Clinical Centre of Serbia and Belgrade University School of Medicine, Belgrade, Serbia f Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa b c
a r t i c l e
i n f o
Article history: Received 19 September 2017 Accepted 13 October 2017 Available online xxxx Keywords: Intrapericardial fibrinolysis Pericardial effusion Pericarditis
a b s t r a c t Pericardial effusion is the abnormal accumulation of fluid in the pericardial space. The complications of pericardial effusion can either be acute (e.g., cardiac tamponade) or chronic (e.g., constrictive pericarditis). We have conducted a systematic review of the scientific literature to evaluate the efficacy and safety of intrapericardial fibrinolysis in preventing complications of pericardial effusion. We searched for both published and unpublished studies. 29 studies, with a total of 109 patients were included in this review; 17 case reports, 11 case series, and one randomised controlled trial (RCT). All included studies had a high risk of bias. The most common causes of pericardial effusion were Staphylococcus aureus (12 studies with 23 cases) and Mycobacterium tuberculosis (2 studies with 19 cases). The most common fibrinolytic agents used were streptokinase (15 studies) and urokinase (5 studies). Intrapericardial fibrinolysis prevented complications in 94 (86.2%) patients. Non-fatal procedure-related complications were reported 21 (19.2%) patients. No patient died following intrapericardial fibrinolysis. There is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. High quality RCTs are required to address this question. © 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Pericardial effusion is the abnormal accumulation of fluid in the pericardial space due to either a known or an unknown (idiopathic) cause [1]. Causes of pericardial effusion include infection, cancer, connective tissue disease, pericardial injury, metabolic derangement, myopericardial disease, and aortic disease [2]. The complications of pericardial effusion are persistent effusion, cardiac tamponade, recurrence of effusion, constrictive pericarditis, and death [3,4]. Studies reporting the management of pericardial effusion using non-steroidal anti-inflammatory drugs (NSAIDs) in association with colchicine, corticosteroids [5], azathioprine, cyclophosphamide and anakinra have produced variable results [4]. Re-accumulation rates tend to be high following pericardiocentesis which is currently the treatment of ⁎ Corresponding author: E-mail addresses: [email protected] (A.B. Wiyeh), [email protected] (E.A. Ochodo), [email protected] (C.S. Wiysonge), [email protected] (A. Ristic), [email protected] (B.M. Mayosi).
choice [6]. Over the past 20 years, intrapericardial fibrinolysis has been increasingly used in patients with effusive pericarditis, with promising results [3]. Our objective was to determine the efficacy and safety of this intervention when used to prevent or treat complications in patients with pericardial effusion. This systematic review was registered in PROSPERO (CRD4201 4015238) and the protocol published [7]. We searched for all primary studies that met our eligibility criteria, irrespective of the language of publication. Studies carried out on people of all ages and both sexes, with pericardial effusion due to any cause, were included. Fibrinolytic agents administered intrapericardially alone or in combination with any other intervention were compared to placebo, no intervention or any other intervention to prevent complications of pericardial effusion. The primary outcomes were cardiac tamponade, persistent or recurrent pericardial effusion, and constrictive pericarditis. Other outcomes included procedure related complications (incidence of haemorrhage, procedure-related cardiac tamponade, allergic reactions, and adverse events), long-term complications, and death.
https://doi.org/10.1016/j.ijcard.2017.10.049 0167-5273/© 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Table 1 Table of general study characteristics. Study ID
Country
Study Number of design patents
Population Age
Sex
Preceding/associated Pathologies
Aetiology
Modality of diagnosis
Complications of pericardial effusion present prior to intervention
Dybowska 2015
Poland
CR
1
63 yrs
M
Purulent inflammation of the right knee
Unknown. Cultures and Mycobacterium tuberculosis tests were negative
Ideh 2014
The Gambia CR
1
9 yrs
M
Staphylococcus aureus
Lee 2014
Taiwan
CR
1
60 yrs
M
Staphylococcus aureus
Echocardiography None reported
Abamukov 2010
Russia
CS
92 M & 8F
Unclear
Echocardiography None reported
Bigham 2008
USA
CR
15–82 100 (Only 7 yrs got the intervention) 1 4m
Staphylococcus aureus
Echocardiography Recurrence
Johnson 2007 Cui 2005
USA China
CR RCT
79 yrs 9 yr to 66 yrs
F 23 M & 24 F
Ekim 2004
Turkey
CS
1 94 (47 got the intervention) 9
Treated for pneumonia, malaria Abscesses over the right chest wall and prostate, hyperglycemia Trauma(79 stab thoracic and 29 blunt thoracic trauma) Glycogen storage disease type IB Mesothelioma Not stated
Echocardiography None before streptokinase and Pericardial Constriction prior to tPA Echocardiography Recurrence
3 yrs to 13 yrs
5 M &4 F
Echocardiography Recurrence Echocardiography Tamponade (11) & pericardial calcifications [8] Echocardiography Tamponade in 4 patients
Tomkowski 2004
Poland
CS
3
40 yrs to 1 M & 2 F 64 yrs
Reznikoff 2003 Tomkowski 2003 Zimmerman 2003 Kamimura 2002
USA Poland
CR CR
1 1
61 yrs 50 yrs
M M
Periorbital abscess Purulent tonsillitis
mesothelioma 18 due to Mycobacterium tuberculosis and 29 purulent pericarditis Staphylococcus aureus in 2 patients and negative bacteriologic cultures in 7 patients Patient 1: Streptococcus species. Culture was negative for patient 2. Streptococcus intermedius, Enterococcus feacalis for patient 3 Staphylococcus aureus Streptococcus species
Germany
CR
1
23 yrs
M
Japan
CR
1
41 yrs
male
Hodgin's disease and C-protein deficiency Unsterilized deep skin fistula
Keersmakers 2002
Belgium
CR
1
36 yrs
M
Unknown
Ustonsoy 2002
Turkey
CS
9
5 yr to 50 yrs
5M&4F
Omer 2002
Turkey
CS
3
10 m,18 m &4 yrs
1M&2F
7 had extra cardiac infections, 1 had heart surgery for ASD, &one had DM Respiratory infections in 2 out of 3
Schafer 2002
Switzerland CR
1
39 yrs
M
Acute bronchitis Unclear
F
Bronchopulmonary infections in 8 and septic arthritis in 1 patient Peri-tonsillar abscess in patient 1, prolonged use of corticosteroids in patient 2, Pneumonia in patient 3.
Bridgman 2001 New Zealand Svendsen 2001 Norway Juneja 1999 India
CR
1
61 yrs
F
CSa CS
1 6
67 yrs 8 m to 12 yrs
Defouilloy1997 France
CS
2
16 yrs and 38 yrs
F Osteomyelitis Unknown extra cardiac infections in 2 (arthritis, osteomyelitis and parietal abscesses) M Oesophageal squamous carcinoma for patient 1 and flulike symptoms for patient 2
Maynar 1997
Spain
CR
1
78 yrs
F
Not stated
Mann-Segal 1996 Winkler 1994
Australia
CR
1
76 yrs
M
lingular harmatoma
Austria
CS
3
21, 38 & 54 yrs
M
Patient 1:Mediastinitis and septic shock, patient 2: cirrhosis,
Echocardiography None
Echocardiography None Echocardiography None
Unknown
Echocardiography None
Mycobacterium tuberculosis. Secondary bacterial pericarditis with α- Streptococcus Streptococcus viridans
Chest computed tomography
Staphylococcus aureus in 8 patients and 1 unknown Staphylococcus aureus in 1 patient and unknown in rest. Unknown (sterile cultures)
None
Transthoracic and None Transoesophageal Echocardiography Echocardiography 1 patient had Tamponade
Echocardiography None
Echocardiography Recurrence
Echocardiography Recurrence Staphylococcus aureus Streptococcus pneumoniae Echocardiography None Echocardiogram None 4 patients had Staphylococcus aureus infection Unknown
Echocardiography Constrictive pericarditis for patient 1 and cardiac tamponade for patient 2 Streptococcus pneumoniae Transthoracic Cardiac Echocardiography tamponade Staphylococcus aureus Echocardiography Cardiac tamponade Echocardiography None Patient 1: Bacteroides species) and Patient 2: Staphylococcus
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Table 1 (continued) Study ID
Country
Study Number of design patents
Population Age
Sex
Preceding/associated Pathologies
Aetiology
aureus.
Cross 1989
UK
CR
1
20 m
M
Schweitzer 1956
USA
CR
1
26 yrs
M
patient 3: meningitis/ pneumonia Noonan's syndrome, severe valvar pulmonary stenosis, hypertrophic obstructive cardiomyopathy. Chest trauma
Lundstrom 1955 Adie 1951
Sweden
CR
1
6 yrs.
F
Acute sore throat
USA
CSa
1
35 yrs
M
Right upper lobe lesion
Wright 1951
USA
CSa
1
34 yrs
F
Stab wound of the heart
Modality of diagnosis
Complications of pericardial effusion present prior to intervention
Not stated
Echocardiography Reocurrence and tamponade
Pseudomonas aeruginosa and Staphylococcus aureus Haemophilus influenzae
Chest X-rays and physical examination Chest roentgenogram Chest X-ray
Cardiac tamponade
Chest X-ray
None
Negative smear and culture Streptococcus viridans
None None
a
CR: case report, CS: case series, : case series but only one patient had intrapericardial fibrinolysis, yrs: years, M: male, F: female, m: months.
2. Methods Key terms were used to develop a comprehensive search strategy. This strategy was used to search PubMed, Cochrane Library, AJOL, CINAHL, and TRIP database on November 2016. We also screened the reference lists of relevant previously published reviews, contacted experts in the field of therapeutic pericardiocentesis, and searched Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform for potential articles. Studies were selected and extracted following Cochrane methodology as described in the Cochrane handbook [8]. The risk of bias and methodological quality were assessed using the Cochrane tool for RCTs [8]. Joanna Briggs Institute (JBI) Critical Appraisal Checklists for case series and case reports respectively [9,10].
3. Results Our search retrieved a total of 4697 studies. We excluded 4657 studies after screening titles, abstracts and removing duplicates. We assessed 40 full texts for eligibility and excluded 11 studies with reasons. We excluded 3 reviews, and two letters to the editor. In four studies the authors did not use a fibrinolytic agent, and the fibrinolytic agent was not administered intrapericardially in two studies. We included 29 studies; seventeen case reports, eleven case series, and one randomized study. In three of the case series, only one participant met our inclusion criteria. Of the 29 included studies, 22 studies were conducted in high income settings. Only one study was carried out in Africa. There was a total of 109 participants, with the ages ranging between 4 months and 79 years. We included 26 English studies, and one article each in German, Russian and Norwegian, respectively. In 54 of the 109 participants included, there was a reported preceding illness associated with the diagnosis of pericardial effusion. These included respiratory tract infections, chest wall infections, infections of the head and neck region, and osteomyelitis. Some had a history of chest injury and others of malignancy. Other associated pathologies described include glycogen storage disease type IB, hyperglycaemia and cardiomyopathies. The aetiology was infectious in 51 patients: Staphylococcus aureus (n = 23 patients in 12 studies), Mycobacterium tuberculosis (n = 19 patients in 2 studies), Streptococcus species (n = 8 patients in 7 studies), Haemophilus influenzae (n = 1 patient), Pseudomonas aeruginosa (n = 1 patient), and Bacteroides species (n = 1 patient), and Enterococcus feacalis (n = 1 patient). In three patients, two different organisms were isolated from the pericardial fluid. There was only one case of pericardial effusion reported as being due to a malignancy. In 25 out of the 29 studies, pericardial effusion was diagnosed using echocardiography. Prior to fibrinolysis, some of the patients had already developed cardiac tamponade (n = 20), reoccurrence of pericardial effusion (n = 5), and pericardial constriction (n = 2). One patient had both a pericardial
effusion that reoccurred and cardiac tamponade. These are described in Table 1. The included randomized trial had an unclear risk of bias for sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors and other sources of bias. It had a high risk of bias for incomplete outcome data and selective outcome reporting. Based on these, the study was considered to have a high overall risk of bias. There were three case series in which only one patient had intrapericardial fibrinolysis. These three studies were appraised using the tool for case reports. The remaining eight cases series were appraised using the tool for case series. Most studies scored ‘yes’ in the following domains: clear inclusion criteria, valid identification methods, clinical information of participants and outcomes/follow up results. However, the majority of authors failed to properly report the participant's demographics and study site information. Twenty included studies (17 case reports and 3 case series) were assessed using the tool for case reports. All studies described the patient's demographics properly. However, most authors did not report the patient's post intervention clinical condition adequately. The quality of reporting was better in the more recently published studies than the older ones. The intrapericardial fibrinolytic agents used in the included studies were: streptokinase (n = 15 studies), urokinase (n = 5 studies), tissue plasminogen activator (tPA) (n = 2 studies), tenecteplase (n = 1 study), streptokinase and tPA successively (n = 1 study), and streptokinase and streptodornase (n = 5 study). There was heterogeneity in the doses, volume, frequency, and duration of treatment within and between included studies as seen in Table 2. In studies where streptokinase was used alone, the dose administered ranged from 10.000 units to 500.000 units (and 2000 u/kg to 18.000 u/kg in the paediatric age group). Smaller doses of streptokinase were used when streptokinase was administered concomitantly with streptodornase. Intrapericardial fibrinolysis was successful in preventing the occurrence of complications of pericardial effusion in 94 out of 109 participants (86.2%). Amongst the 15 patients who developed complications, some developed pericardial constriction (n = 9), others had a persistent pericardial effusion (n = 4) and some developed cardiac tamponade (n = 2). There was one patient in whom initial therapy with a single dose of streptokinase failed, but successive treatment with tPA was successful in draining the pericardium. We considered the outcome to be favourable in this patient. Outcomes were unfavourable in 5 out of 47 patients on streptokinase (10.6%) and 10 out of 53 patients on urokinase (18.9%). Treatment was favourable in all the patients who received tPA, tenecteplase, and streptokinase/ streptodornase.
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Table 2 Table of intervention details. Study ID
Indication
Streptokinase Ideh 2014 Unknown Abamukov 2010 Tomkowski 2004
Fibrinolytic agent used
Total dose administered
Favorable outcomes
Procedure related complications
Long term complications
Streptokinase
18,000 i.u/kg (375,000 i.u.) × 2 doses left in situ for 2 h 150,000 U/day for 3–5 days
Yes
None reported
Yes (in 5 out of 7 cases)
Blood tinged aspirate believed not to be due to the procedure None reported
Unknown
Streptokinase
Due to considerable purulent pericardial drainage, loculations and fibrin deposits To obliterate the loculations and fibrin strands Due to failure of pericardiocentesis Due to huge pericardial drainage and presence of fibrin deposits Unknown
Streptokinase
500,000 units × 3 doses, drain clamped till next dose 12 h later.
Yes
None reported
None reported
Streptokinase
15,000 to 18,000 units/kg and drain clamped for 2 h post instillation. Total number of doses unclear 75,000 units bd for 4 days
Yes
None reported
None reported
Yes
None reported
None reported
Streptokinase
500,000 IU × 3 doses, drain clamped Yes till the next dose
None reported
None reported
Streptokinase
2000 U/kg daily × 5 doses
Yes
None reported
None reported
Unknown
Streptokinase
10,000 units/kg dose × 3–8 days
Yes
None reported
Due to poor drainage
Streptokinase
300,000 U × 5 doses
Poor drainage due to fibrin Unknown
Streptokinase
10,000 IU × 3doses
No. patient developed tamponade Yes
Hemorrhagic fluid in intrapericardial tube drainage of one patient Atrial fibrillations, tamponade Blood tinged aspirate
None reported
Streptokinase
None reported
Streptokinase
No. echo appearances were unchanged Yes
None reported
Unknown
100,000 units × 3 doses. Drain clamped for 1 h post instillation 8000–15,000 units/kg × 4–8 days
Streptokinase
250,000 IU × 4 doses for patient 1 and 2 doses for patient 2
Failed in patient 1 and efficient in patient 2
Maynar 1997 Cross 1989
Patient 1: patients poor general status patient 2: Unknown Unknown
Streptokinase
Yes
Hemorrhagic fluid was observed
None reported
Unknown
Streptokinase
250,000 units × 3doses, drain clamped for 1 h after instillation 2000 U/kg daily × 2 doses, drained clamped for 3 h
Yes
None reported
None reported
Urokinase Lee 2014
Unknown
Urokinase
No. patient developed cardiac tamponade Yes. nine cases in experimental versus 27 cases in control developed pericardial constriction
Tamponade
None reported
Intrapericardial bleeding in 6 out of 47 patients in experimental group though could not be attributed to intervention
None reported
Yes
None reported
None reported
Yes
Fistula formation between the pericardium and right pleural cavity Patient 1: the last portion of mobilized fluid was blood tinged viscous fluid.
None reported
Ekim 2004
Zimmerman 2003 Tomkowski 2003
Ustonsoy 2002 Omer 2002
Keersmakers 2002 Svendsen 2001 Bridgman 2001 Juneja 1999
Defouilloy 1997
Streptokinase
40,000 units. Total number of doses unknown 200,000 units – 600,000 units, clamped for 1 h, then sucked out plus pericardiocentesis and drainage for intervention group versus pericardiocentesis and drainage for control group. 400,000 U of Urokinase initially followed by 3 × 200,000 U/day for 4 days and Prednisone 1 mg/kg body weight 120,000 units × 5 doses, drain clamped for 12 h after instillation
Cui 2005
Urokinase
Schafer 2002 To drain the fibrino-purulent effusion and prevent its reoccurrence Kamimura Unknown 2002
Urokinase and systemic prednisone
Winkler 1994
Urokinase
yes For patient 1: 400,000 U × 2 doses. For patient 2, 400,000 U × 3 doses and 2,200,000 × 2 doses. For patient 3: 400,000 U × 1 dose and 200,000 × 17 doses. The drain clamped for 1 h after instillation.
tPA
2 mg diluted in 10 ml and 6 ml was Yes given. Then 1 mg in 5 ml given 12 h later, and a last dose of 1 mg in 5 ml, with drain clamped for 2 h after instillation 30 mg × 1 dose Yes
For complete drainage that could not be obtained by pericardiocentesis
Tissue plasminogen activator (tPA) Bigham Unknown 2008
Reznikoff 2003
Due to poor drainage suspected to be as a
Urokinase
tPA
None reported
None reported
None reported Intrapericardial hemorrhage occurred in one child, and later development of submitral pseudoaneurysm and tamponade. 2 patients developed a right atrial mass after onset of streptokinase None reported None reported
None. Patient 2 later died of hepatic coma
Marked hypotension with narrowing of pulse pressures
None reported
None reported
None reported
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Table 2 (continued) Study ID
Indication
Fibrinolytic agent used
Total dose administered
Favorable outcomes
Procedure related complications
Long term complications
Tenecteplase
15 mg,7,5 mg,7,5 mg (total of 3 doses) allowed to dwell in situ for 2 h after first dose and 1 h after the second dose
yes
New onset atrial fibrillations
None reported
Streptokinase and tPA,
500,000 units × 1 dose for streptokinase with clamping for 12 h post instillation. 20 mg × 2 doses, and drain clamped for 24 h for TPA
Growing constriction of Severe retrosternal chest pain with streptokinase the pericardium after streptokinase was interrupted (due to complications). tPA was efficient.
None reported
Yes
None reported
None reported
Yes
None reported
None reported
yes
Moderate systemic disturbances and chills, Febrile reactions
None reported
Yes
None reported
None. Patient later died of lymphosarcoma
Yes
None reported
None reported
result of loculated fluid or fibrinous material blocking the drain Tenecteplase Johnson 2007
To enhance drainage and prevent re-accumulation
Streptokinase and tPA Dybowska Streptokinase given 2015 to prevent constrictive pericarditis and TPA due to growing signs of constriction
Streptokinase and streptodornase Mann-Segal No drainage obtained Streptokinase 1996 on pericardiocentesis and Streptodornase Schweitzer Due to poor drainage Streptokinase, streptodornase 1956 and increasing signs and bactracin of increasingly evident signs of cardiac tamponade
Lundstrom 1955
Poor drainage due to fibrin
Adie 1951
Unknown
Wright 1951
Unknown
100,000 units Streptokinase and 25,000 units of streptodornase. Total number of doses unclear 30,000 units of Streptokinase and 10,000 units of streptodornase with bacitracin, followed by daily irrigations with 100,000 units of Streptokinase, 25,000 units of streptodornase and 25,000 units of bacitracin, then 20,000 units of streptokinase, 50,000 units of streptodornase and 25,000 units of bacitracin in 30 cm3. Total number of doses unclear 100,000 units of streptokinase and Streptokinase 25,000 units of streptodornase and Streptodornase intrapericardially, followed by one half of the aforementioned quantity on subsequent occasions/ × 7 doses 200,000 units of streptokinase and Streptokinase 75,000 units of streptodornase × 6 and streptodornase doses for each, drain clamped for 8 h on alternate days 3.2 million U of Streptokinase and Streptokinase 1,2 million U of streptodornase × 4 and streptodornase doses
4. Discussion This review extends the work of Augustin et al.[3] and Imazio et al.,[4] by including all causes of pericardial effusion. Augustin et al. report a failure rate of 5% after using intrapericardial fibrinolysis in the management of purulent fibrinolysis.[3] Our study reports a higher failure rate of 13.8%, probably because we included other causes of pericardial effusion such as tuberculous pericarditis. There were short term complications observed in 21 patients with haemorrhage (n = 12) being the most frequent. The complications reported were similar in patients who had been administered both streptokinase and urokinase. However, it was difficult to determine if these complications were due to fibrinolysis or pericarditis. Two patients died from hepatic coma and lymphosarcoma: causes not related to intrapericardial fibrinolysis. The details of the interventions are described in Table 2. The findings of this review suggest that there is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. The certainty of the evidence is limited because the majority of included studies are case reports and case series, which inherently have serious risks of bias. In addition the single RCT which was included was judged as having a high risk of
bias. The very low certainty of the evidence implies that we are very uncertain about the estimate of effect of the intervention. In the study protocol, we had planned to carry out a meta-analysis, which was not possible due to the types of articles found. We recommend that randomized controlled studies should be conducted, in low, middle and high income settings to address this question. Also, this promising intervention should be tested in patients with pericardial effusions of varied aetiologies as the majority of patients had effusions of infectious origin. Finally, researchers should focus on identifying the safe and effective doses of the various fibrinolytics at which the agents are both effective and safe. A trial of intrapericardial alteplase in large pericardial effusion (IMPI-2) is underway to address this question (ClinicalTrials.gov Identifier: NCT02673879). Acknowledgements This work is based on the research supported in part by the South African Medical Research Council, National Research Foundation of South Africa (Grant numbers 106035 and 108571), and Stellenbosch University. Eleanor Ochodo is funded by the Wellcome Trust Foundation (Grant number 109939). Wellcome Trust had no role in the design, conduct or publication of the review.
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
All the authors materially participated in the research and article preparation and declare no conflict of interests.
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[Internet][cited 2016 Jul 27];371(12):1121–30. Available from http://www.ncbi. nlm.nih.gov/pubmed/25178809 2014 Sep 18. P.M. Seferović, A.D. Ristić, R. Maksimović, D.S. Simeunović, I. Milinković, J.P. Seferović Mitrović, et al., Pericardial syndromes: an update after the ESC guidelines 2004, Heart Fail Rev [Internet] 18 (3) (2013 May 2) 255–266 Springer US. [cited 2016 Jul 21]. Available from http://link.springer.com/10.1007/s10741-012-9335-x. A. Kakia, C.S. Wiysonge, E.A. Ochodo, A.A. Awotedu, A.D. Ristic, B.M. Mayosi, The efficacy and safety of complete pericardial drainage by means of intrapericardial fibrinolysis for the prevention of complications of pericardial effusion: a systematic review protocol, BMJ Open [Internet] 6 (1) (2016) [cited 2016 Aug 10]. e007842. Available from http://www.ncbi.nlm.nih.gov/pubmed/26733562. The Cochrane Collaboration, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] [Internet], in: J.P.T. Higgins, S. Green (Eds.),The Cochrane Collaboration, 2011 (Available from: http://handbook. cochrane.org). The Joanna Briggs Institute, The Joanna Briggs Institute Critical Appraisal tool for use in JBI Systematc reviews, Checklit for Case Series, 2016 [cited 2017 Apr 17]; Available from http://joannabriggs.org/research/critical/appraisal/tools.html. M. Dybowska, B. Kazanecka, P. Kuca, J. Burakowski, C. Czajka, F. Grzegorczyk, et al., Intrapericardial fibrinolysis in purulent pericarditis-case report, Int J Emerg Med [Internet] 8 ((1):36) (2015 Dec) [cited 2016 Aug 10]. Available from http://www. ncbi.nlm.nih.gov/pubmed/26446031.
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short communication
A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion Alison B. Wiyeh a,b,⁎, Eleanor A. Ochodo a, Charles S. Wiysonge b, Aloysious Kakia c, Abolade A. Awotedu d, Arsen Ristic e, Bongani M. Mayosi f a
Centre for Evidence-based Health Care, Department of Global Health, Stellenbosch University, Cape Town, South Africa Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa Department of Family Medicine and Rural Health, Walter Sisulu University, Mthatha, South Africa d Department of Medicine, Nelson Mandela Academic Hospital and Walter Sisulu University, Mthatha, South Africa e Department of Cardiology, Clinical Centre of Serbia and Belgrade University School of Medicine, Belgrade, Serbia f Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa b c
a r t i c l e
i n f o
Article history: Received 19 September 2017 Accepted 13 October 2017 Available online xxxx Keywords: Intrapericardial fibrinolysis Pericardial effusion Pericarditis
a b s t r a c t Pericardial effusion is the abnormal accumulation of fluid in the pericardial space. The complications of pericardial effusion can either be acute (e.g., cardiac tamponade) or chronic (e.g., constrictive pericarditis). We have conducted a systematic review of the scientific literature to evaluate the efficacy and safety of intrapericardial fibrinolysis in preventing complications of pericardial effusion. We searched for both published and unpublished studies. 29 studies, with a total of 109 patients were included in this review; 17 case reports, 11 case series, and one randomised controlled trial (RCT). All included studies had a high risk of bias. The most common causes of pericardial effusion were Staphylococcus aureus (12 studies with 23 cases) and Mycobacterium tuberculosis (2 studies with 19 cases). The most common fibrinolytic agents used were streptokinase (15 studies) and urokinase (5 studies). Intrapericardial fibrinolysis prevented complications in 94 (86.2%) patients. Non-fatal procedure-related complications were reported 21 (19.2%) patients. No patient died following intrapericardial fibrinolysis. There is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. High quality RCTs are required to address this question. © 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Pericardial effusion is the abnormal accumulation of fluid in the pericardial space due to either a known or an unknown (idiopathic) cause [1]. Causes of pericardial effusion include infection, cancer, connective tissue disease, pericardial injury, metabolic derangement, myopericardial disease, and aortic disease [2]. The complications of pericardial effusion are persistent effusion, cardiac tamponade, recurrence of effusion, constrictive pericarditis, and death [3,4]. Studies reporting the management of pericardial effusion using non-steroidal anti-inflammatory drugs (NSAIDs) in association with colchicine, corticosteroids [5], azathioprine, cyclophosphamide and anakinra have produced variable results [4]. Re-accumulation rates tend to be high following pericardiocentesis which is currently the treatment of ⁎ Corresponding author: E-mail addresses: [email protected] (A.B. Wiyeh), [email protected] (E.A. Ochodo), [email protected] (C.S. Wiysonge), [email protected] (A. Ristic), [email protected] (B.M. Mayosi).
choice [6]. Over the past 20 years, intrapericardial fibrinolysis has been increasingly used in patients with effusive pericarditis, with promising results [3]. Our objective was to determine the efficacy and safety of this intervention when used to prevent or treat complications in patients with pericardial effusion. This systematic review was registered in PROSPERO (CRD4201 4015238) and the protocol published [7]. We searched for all primary studies that met our eligibility criteria, irrespective of the language of publication. Studies carried out on people of all ages and both sexes, with pericardial effusion due to any cause, were included. Fibrinolytic agents administered intrapericardially alone or in combination with any other intervention were compared to placebo, no intervention or any other intervention to prevent complications of pericardial effusion. The primary outcomes were cardiac tamponade, persistent or recurrent pericardial effusion, and constrictive pericarditis. Other outcomes included procedure related complications (incidence of haemorrhage, procedure-related cardiac tamponade, allergic reactions, and adverse events), long-term complications, and death.
https://doi.org/10.1016/j.ijcard.2017.10.049 0167-5273/© 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Table 1 Table of general study characteristics. Study ID
Country
Study Number of design patents
Population Age
Sex
Preceding/associated Pathologies
Aetiology
Modality of diagnosis
Complications of pericardial effusion present prior to intervention
Dybowska 2015
Poland
CR
1
63 yrs
M
Purulent inflammation of the right knee
Unknown. Cultures and Mycobacterium tuberculosis tests were negative
Ideh 2014
The Gambia CR
1
9 yrs
M
Staphylococcus aureus
Lee 2014
Taiwan
CR
1
60 yrs
M
Staphylococcus aureus
Echocardiography None reported
Abamukov 2010
Russia
CS
92 M & 8F
Unclear
Echocardiography None reported
Bigham 2008
USA
CR
15–82 100 (Only 7 yrs got the intervention) 1 4m
Staphylococcus aureus
Echocardiography Recurrence
Johnson 2007 Cui 2005
USA China
CR RCT
79 yrs 9 yr to 66 yrs
F 23 M & 24 F
Ekim 2004
Turkey
CS
1 94 (47 got the intervention) 9
Treated for pneumonia, malaria Abscesses over the right chest wall and prostate, hyperglycemia Trauma(79 stab thoracic and 29 blunt thoracic trauma) Glycogen storage disease type IB Mesothelioma Not stated
Echocardiography None before streptokinase and Pericardial Constriction prior to tPA Echocardiography Recurrence
3 yrs to 13 yrs
5 M &4 F
Echocardiography Recurrence Echocardiography Tamponade (11) & pericardial calcifications [8] Echocardiography Tamponade in 4 patients
Tomkowski 2004
Poland
CS
3
40 yrs to 1 M & 2 F 64 yrs
Reznikoff 2003 Tomkowski 2003 Zimmerman 2003 Kamimura 2002
USA Poland
CR CR
1 1
61 yrs 50 yrs
M M
Periorbital abscess Purulent tonsillitis
mesothelioma 18 due to Mycobacterium tuberculosis and 29 purulent pericarditis Staphylococcus aureus in 2 patients and negative bacteriologic cultures in 7 patients Patient 1: Streptococcus species. Culture was negative for patient 2. Streptococcus intermedius, Enterococcus feacalis for patient 3 Staphylococcus aureus Streptococcus species
Germany
CR
1
23 yrs
M
Japan
CR
1
41 yrs
male
Hodgin's disease and C-protein deficiency Unsterilized deep skin fistula
Keersmakers 2002
Belgium
CR
1
36 yrs
M
Unknown
Ustonsoy 2002
Turkey
CS
9
5 yr to 50 yrs
5M&4F
Omer 2002
Turkey
CS
3
10 m,18 m &4 yrs
1M&2F
7 had extra cardiac infections, 1 had heart surgery for ASD, &one had DM Respiratory infections in 2 out of 3
Schafer 2002
Switzerland CR
1
39 yrs
M
Acute bronchitis Unclear
F
Bronchopulmonary infections in 8 and septic arthritis in 1 patient Peri-tonsillar abscess in patient 1, prolonged use of corticosteroids in patient 2, Pneumonia in patient 3.
Bridgman 2001 New Zealand Svendsen 2001 Norway Juneja 1999 India
CR
1
61 yrs
F
CSa CS
1 6
67 yrs 8 m to 12 yrs
Defouilloy1997 France
CS
2
16 yrs and 38 yrs
F Osteomyelitis Unknown extra cardiac infections in 2 (arthritis, osteomyelitis and parietal abscesses) M Oesophageal squamous carcinoma for patient 1 and flulike symptoms for patient 2
Maynar 1997
Spain
CR
1
78 yrs
F
Not stated
Mann-Segal 1996 Winkler 1994
Australia
CR
1
76 yrs
M
lingular harmatoma
Austria
CS
3
21, 38 & 54 yrs
M
Patient 1:Mediastinitis and septic shock, patient 2: cirrhosis,
Echocardiography None
Echocardiography None Echocardiography None
Unknown
Echocardiography None
Mycobacterium tuberculosis. Secondary bacterial pericarditis with α- Streptococcus Streptococcus viridans
Chest computed tomography
Staphylococcus aureus in 8 patients and 1 unknown Staphylococcus aureus in 1 patient and unknown in rest. Unknown (sterile cultures)
None
Transthoracic and None Transoesophageal Echocardiography Echocardiography 1 patient had Tamponade
Echocardiography None
Echocardiography Recurrence
Echocardiography Recurrence Staphylococcus aureus Streptococcus pneumoniae Echocardiography None Echocardiogram None 4 patients had Staphylococcus aureus infection Unknown
Echocardiography Constrictive pericarditis for patient 1 and cardiac tamponade for patient 2 Streptococcus pneumoniae Transthoracic Cardiac Echocardiography tamponade Staphylococcus aureus Echocardiography Cardiac tamponade Echocardiography None Patient 1: Bacteroides species) and Patient 2: Staphylococcus
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
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Table 1 (continued) Study ID
Country
Study Number of design patents
Population Age
Sex
Preceding/associated Pathologies
Aetiology
aureus.
Cross 1989
UK
CR
1
20 m
M
Schweitzer 1956
USA
CR
1
26 yrs
M
patient 3: meningitis/ pneumonia Noonan's syndrome, severe valvar pulmonary stenosis, hypertrophic obstructive cardiomyopathy. Chest trauma
Lundstrom 1955 Adie 1951
Sweden
CR
1
6 yrs.
F
Acute sore throat
USA
CSa
1
35 yrs
M
Right upper lobe lesion
Wright 1951
USA
CSa
1
34 yrs
F
Stab wound of the heart
Modality of diagnosis
Complications of pericardial effusion present prior to intervention
Not stated
Echocardiography Reocurrence and tamponade
Pseudomonas aeruginosa and Staphylococcus aureus Haemophilus influenzae
Chest X-rays and physical examination Chest roentgenogram Chest X-ray
Cardiac tamponade
Chest X-ray
None
Negative smear and culture Streptococcus viridans
None None
a
CR: case report, CS: case series, : case series but only one patient had intrapericardial fibrinolysis, yrs: years, M: male, F: female, m: months.
2. Methods Key terms were used to develop a comprehensive search strategy. This strategy was used to search PubMed, Cochrane Library, AJOL, CINAHL, and TRIP database on November 2016. We also screened the reference lists of relevant previously published reviews, contacted experts in the field of therapeutic pericardiocentesis, and searched Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform for potential articles. Studies were selected and extracted following Cochrane methodology as described in the Cochrane handbook [8]. The risk of bias and methodological quality were assessed using the Cochrane tool for RCTs [8]. Joanna Briggs Institute (JBI) Critical Appraisal Checklists for case series and case reports respectively [9,10].
3. Results Our search retrieved a total of 4697 studies. We excluded 4657 studies after screening titles, abstracts and removing duplicates. We assessed 40 full texts for eligibility and excluded 11 studies with reasons. We excluded 3 reviews, and two letters to the editor. In four studies the authors did not use a fibrinolytic agent, and the fibrinolytic agent was not administered intrapericardially in two studies. We included 29 studies; seventeen case reports, eleven case series, and one randomized study. In three of the case series, only one participant met our inclusion criteria. Of the 29 included studies, 22 studies were conducted in high income settings. Only one study was carried out in Africa. There was a total of 109 participants, with the ages ranging between 4 months and 79 years. We included 26 English studies, and one article each in German, Russian and Norwegian, respectively. In 54 of the 109 participants included, there was a reported preceding illness associated with the diagnosis of pericardial effusion. These included respiratory tract infections, chest wall infections, infections of the head and neck region, and osteomyelitis. Some had a history of chest injury and others of malignancy. Other associated pathologies described include glycogen storage disease type IB, hyperglycaemia and cardiomyopathies. The aetiology was infectious in 51 patients: Staphylococcus aureus (n = 23 patients in 12 studies), Mycobacterium tuberculosis (n = 19 patients in 2 studies), Streptococcus species (n = 8 patients in 7 studies), Haemophilus influenzae (n = 1 patient), Pseudomonas aeruginosa (n = 1 patient), and Bacteroides species (n = 1 patient), and Enterococcus feacalis (n = 1 patient). In three patients, two different organisms were isolated from the pericardial fluid. There was only one case of pericardial effusion reported as being due to a malignancy. In 25 out of the 29 studies, pericardial effusion was diagnosed using echocardiography. Prior to fibrinolysis, some of the patients had already developed cardiac tamponade (n = 20), reoccurrence of pericardial effusion (n = 5), and pericardial constriction (n = 2). One patient had both a pericardial
effusion that reoccurred and cardiac tamponade. These are described in Table 1. The included randomized trial had an unclear risk of bias for sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors and other sources of bias. It had a high risk of bias for incomplete outcome data and selective outcome reporting. Based on these, the study was considered to have a high overall risk of bias. There were three case series in which only one patient had intrapericardial fibrinolysis. These three studies were appraised using the tool for case reports. The remaining eight cases series were appraised using the tool for case series. Most studies scored ‘yes’ in the following domains: clear inclusion criteria, valid identification methods, clinical information of participants and outcomes/follow up results. However, the majority of authors failed to properly report the participant's demographics and study site information. Twenty included studies (17 case reports and 3 case series) were assessed using the tool for case reports. All studies described the patient's demographics properly. However, most authors did not report the patient's post intervention clinical condition adequately. The quality of reporting was better in the more recently published studies than the older ones. The intrapericardial fibrinolytic agents used in the included studies were: streptokinase (n = 15 studies), urokinase (n = 5 studies), tissue plasminogen activator (tPA) (n = 2 studies), tenecteplase (n = 1 study), streptokinase and tPA successively (n = 1 study), and streptokinase and streptodornase (n = 5 study). There was heterogeneity in the doses, volume, frequency, and duration of treatment within and between included studies as seen in Table 2. In studies where streptokinase was used alone, the dose administered ranged from 10.000 units to 500.000 units (and 2000 u/kg to 18.000 u/kg in the paediatric age group). Smaller doses of streptokinase were used when streptokinase was administered concomitantly with streptodornase. Intrapericardial fibrinolysis was successful in preventing the occurrence of complications of pericardial effusion in 94 out of 109 participants (86.2%). Amongst the 15 patients who developed complications, some developed pericardial constriction (n = 9), others had a persistent pericardial effusion (n = 4) and some developed cardiac tamponade (n = 2). There was one patient in whom initial therapy with a single dose of streptokinase failed, but successive treatment with tPA was successful in draining the pericardium. We considered the outcome to be favourable in this patient. Outcomes were unfavourable in 5 out of 47 patients on streptokinase (10.6%) and 10 out of 53 patients on urokinase (18.9%). Treatment was favourable in all the patients who received tPA, tenecteplase, and streptokinase/ streptodornase.
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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Table 2 Table of intervention details. Study ID
Indication
Streptokinase Ideh 2014 Unknown Abamukov 2010 Tomkowski 2004
Fibrinolytic agent used
Total dose administered
Favorable outcomes
Procedure related complications
Long term complications
Streptokinase
18,000 i.u/kg (375,000 i.u.) × 2 doses left in situ for 2 h 150,000 U/day for 3–5 days
Yes
None reported
Yes (in 5 out of 7 cases)
Blood tinged aspirate believed not to be due to the procedure None reported
Unknown
Streptokinase
Due to considerable purulent pericardial drainage, loculations and fibrin deposits To obliterate the loculations and fibrin strands Due to failure of pericardiocentesis Due to huge pericardial drainage and presence of fibrin deposits Unknown
Streptokinase
500,000 units × 3 doses, drain clamped till next dose 12 h later.
Yes
None reported
None reported
Streptokinase
15,000 to 18,000 units/kg and drain clamped for 2 h post instillation. Total number of doses unclear 75,000 units bd for 4 days
Yes
None reported
None reported
Yes
None reported
None reported
Streptokinase
500,000 IU × 3 doses, drain clamped Yes till the next dose
None reported
None reported
Streptokinase
2000 U/kg daily × 5 doses
Yes
None reported
None reported
Unknown
Streptokinase
10,000 units/kg dose × 3–8 days
Yes
None reported
Due to poor drainage
Streptokinase
300,000 U × 5 doses
Poor drainage due to fibrin Unknown
Streptokinase
10,000 IU × 3doses
No. patient developed tamponade Yes
Hemorrhagic fluid in intrapericardial tube drainage of one patient Atrial fibrillations, tamponade Blood tinged aspirate
None reported
Streptokinase
None reported
Streptokinase
No. echo appearances were unchanged Yes
None reported
Unknown
100,000 units × 3 doses. Drain clamped for 1 h post instillation 8000–15,000 units/kg × 4–8 days
Streptokinase
250,000 IU × 4 doses for patient 1 and 2 doses for patient 2
Failed in patient 1 and efficient in patient 2
Maynar 1997 Cross 1989
Patient 1: patients poor general status patient 2: Unknown Unknown
Streptokinase
Yes
Hemorrhagic fluid was observed
None reported
Unknown
Streptokinase
250,000 units × 3doses, drain clamped for 1 h after instillation 2000 U/kg daily × 2 doses, drained clamped for 3 h
Yes
None reported
None reported
Urokinase Lee 2014
Unknown
Urokinase
No. patient developed cardiac tamponade Yes. nine cases in experimental versus 27 cases in control developed pericardial constriction
Tamponade
None reported
Intrapericardial bleeding in 6 out of 47 patients in experimental group though could not be attributed to intervention
None reported
Yes
None reported
None reported
Yes
Fistula formation between the pericardium and right pleural cavity Patient 1: the last portion of mobilized fluid was blood tinged viscous fluid.
None reported
Ekim 2004
Zimmerman 2003 Tomkowski 2003
Ustonsoy 2002 Omer 2002
Keersmakers 2002 Svendsen 2001 Bridgman 2001 Juneja 1999
Defouilloy 1997
Streptokinase
40,000 units. Total number of doses unknown 200,000 units – 600,000 units, clamped for 1 h, then sucked out plus pericardiocentesis and drainage for intervention group versus pericardiocentesis and drainage for control group. 400,000 U of Urokinase initially followed by 3 × 200,000 U/day for 4 days and Prednisone 1 mg/kg body weight 120,000 units × 5 doses, drain clamped for 12 h after instillation
Cui 2005
Urokinase
Schafer 2002 To drain the fibrino-purulent effusion and prevent its reoccurrence Kamimura Unknown 2002
Urokinase and systemic prednisone
Winkler 1994
Urokinase
yes For patient 1: 400,000 U × 2 doses. For patient 2, 400,000 U × 3 doses and 2,200,000 × 2 doses. For patient 3: 400,000 U × 1 dose and 200,000 × 17 doses. The drain clamped for 1 h after instillation.
tPA
2 mg diluted in 10 ml and 6 ml was Yes given. Then 1 mg in 5 ml given 12 h later, and a last dose of 1 mg in 5 ml, with drain clamped for 2 h after instillation 30 mg × 1 dose Yes
For complete drainage that could not be obtained by pericardiocentesis
Tissue plasminogen activator (tPA) Bigham Unknown 2008
Reznikoff 2003
Due to poor drainage suspected to be as a
Urokinase
tPA
None reported
None reported
None reported Intrapericardial hemorrhage occurred in one child, and later development of submitral pseudoaneurysm and tamponade. 2 patients developed a right atrial mass after onset of streptokinase None reported None reported
None. Patient 2 later died of hepatic coma
Marked hypotension with narrowing of pulse pressures
None reported
None reported
None reported
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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Table 2 (continued) Study ID
Indication
Fibrinolytic agent used
Total dose administered
Favorable outcomes
Procedure related complications
Long term complications
Tenecteplase
15 mg,7,5 mg,7,5 mg (total of 3 doses) allowed to dwell in situ for 2 h after first dose and 1 h after the second dose
yes
New onset atrial fibrillations
None reported
Streptokinase and tPA,
500,000 units × 1 dose for streptokinase with clamping for 12 h post instillation. 20 mg × 2 doses, and drain clamped for 24 h for TPA
Growing constriction of Severe retrosternal chest pain with streptokinase the pericardium after streptokinase was interrupted (due to complications). tPA was efficient.
None reported
Yes
None reported
None reported
Yes
None reported
None reported
yes
Moderate systemic disturbances and chills, Febrile reactions
None reported
Yes
None reported
None. Patient later died of lymphosarcoma
Yes
None reported
None reported
result of loculated fluid or fibrinous material blocking the drain Tenecteplase Johnson 2007
To enhance drainage and prevent re-accumulation
Streptokinase and tPA Dybowska Streptokinase given 2015 to prevent constrictive pericarditis and TPA due to growing signs of constriction
Streptokinase and streptodornase Mann-Segal No drainage obtained Streptokinase 1996 on pericardiocentesis and Streptodornase Schweitzer Due to poor drainage Streptokinase, streptodornase 1956 and increasing signs and bactracin of increasingly evident signs of cardiac tamponade
Lundstrom 1955
Poor drainage due to fibrin
Adie 1951
Unknown
Wright 1951
Unknown
100,000 units Streptokinase and 25,000 units of streptodornase. Total number of doses unclear 30,000 units of Streptokinase and 10,000 units of streptodornase with bacitracin, followed by daily irrigations with 100,000 units of Streptokinase, 25,000 units of streptodornase and 25,000 units of bacitracin, then 20,000 units of streptokinase, 50,000 units of streptodornase and 25,000 units of bacitracin in 30 cm3. Total number of doses unclear 100,000 units of streptokinase and Streptokinase 25,000 units of streptodornase and Streptodornase intrapericardially, followed by one half of the aforementioned quantity on subsequent occasions/ × 7 doses 200,000 units of streptokinase and Streptokinase 75,000 units of streptodornase × 6 and streptodornase doses for each, drain clamped for 8 h on alternate days 3.2 million U of Streptokinase and Streptokinase 1,2 million U of streptodornase × 4 and streptodornase doses
4. Discussion This review extends the work of Augustin et al.[3] and Imazio et al.,[4] by including all causes of pericardial effusion. Augustin et al. report a failure rate of 5% after using intrapericardial fibrinolysis in the management of purulent fibrinolysis.[3] Our study reports a higher failure rate of 13.8%, probably because we included other causes of pericardial effusion such as tuberculous pericarditis. There were short term complications observed in 21 patients with haemorrhage (n = 12) being the most frequent. The complications reported were similar in patients who had been administered both streptokinase and urokinase. However, it was difficult to determine if these complications were due to fibrinolysis or pericarditis. Two patients died from hepatic coma and lymphosarcoma: causes not related to intrapericardial fibrinolysis. The details of the interventions are described in Table 2. The findings of this review suggest that there is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. The certainty of the evidence is limited because the majority of included studies are case reports and case series, which inherently have serious risks of bias. In addition the single RCT which was included was judged as having a high risk of
bias. The very low certainty of the evidence implies that we are very uncertain about the estimate of effect of the intervention. In the study protocol, we had planned to carry out a meta-analysis, which was not possible due to the types of articles found. We recommend that randomized controlled studies should be conducted, in low, middle and high income settings to address this question. Also, this promising intervention should be tested in patients with pericardial effusions of varied aetiologies as the majority of patients had effusions of infectious origin. Finally, researchers should focus on identifying the safe and effective doses of the various fibrinolytics at which the agents are both effective and safe. A trial of intrapericardial alteplase in large pericardial effusion (IMPI-2) is underway to address this question (ClinicalTrials.gov Identifier: NCT02673879). Acknowledgements This work is based on the research supported in part by the South African Medical Research Council, National Research Foundation of South Africa (Grant numbers 106035 and 108571), and Stellenbosch University. Eleanor Ochodo is funded by the Wellcome Trust Foundation (Grant number 109939). Wellcome Trust had no role in the design, conduct or publication of the review.
Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049
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A.B. Wiyeh et al. / International Journal of Cardiology xxx (2017) xxx–xxx
All the authors materially participated in the research and article preparation and declare no conflict of interests.
[6]
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Please cite this article as: A.B. Wiyeh, et al., A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2017.10.049