Case Report
Intrapleural Fibrinolysis During Pediatric Extracorporeal Life Support
World Journal for Pediatric and Congenital Heart Surgery 2015, Vol. 6(1) 123-125 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2150135114553478 pch.sagepub.com
Cordelie E. Witt, MD1, Andrew L. Mesher, MD1, Joshua L. Hermsen, MD2, Thomas V. Brogan, MD3, and David Michael McMullan, MD1,2
Abstract Pediatric patients who require extracorporeal life support (ECLS) for refractory cardiorespiratory failure are at increased risk for intrapleural hemorrhage due to the effects of systemic anticoagulation and frequent occurrence of pneumothorax. Surgical evacuation is standard therapy for retained hemothorax to prevent secondary empyema, pulmonary compression, and development of fibrothorax. However, surgical interventions during ECLS are hazardous and place patients at increased risk for surgical site bleeding. Intrapleural fibrinolysis with tissue plasminogen activator may be used to facilitate nonsurgical evacuation of retained hemothorax. We present two pediatric patients who were safely and successfully managed with intrapleural fibrinolysis of retained hemothorax during ECLS. Keywords extracorporeal membrane oxygenation, hemothorax, pleural space, pediatric Submitted June 14, 2014; Accepted September 01, 2014.
Despite improvements in extracorporeal life support (ECLS) circuitry and anticoagulation strategies, up to 30% of highrisk neonates develop hemothorax during ECLS.1 When inadequately evacuated, retained hemothorax may prevent weaning from ECLS and increase the risk of empyema and fibrothorax. Surgical procedures, including thoracoscopic or open surgical drainage of retained intrathoracic blood, are associated with increased risk of hemorrhage and death in this population.2 Intrapleural fibrinolysis using tissue plasminogen activator (TPA) to promote breakdown and evacuation of retained hemothorax is an attractive alternative to surgical drainage in these high-risk patients. We present two patients who underwent successful intrapleural TPA-mediated thrombolysis of retained hemothoraxes during ECLS
Case Reports Patient 1 A previously healthy four-year-old (20 kg) girl was admitted to the intensive care unit for severe respiratory distress due to Streptococcus pneumoniae and human metapneumovirus pneumonia. She was placed on venovenous ECLS via the right internal jugular vein and received systemic anticoagulation by continuous heparin infusion to maintain an activated clotting time (ACT) of 200 to 220 seconds. On the 11th day of ECLS, she developed a large hemothorax after insertion of a small-
bore chest drain to evacuate a spontaneous right pneumothorax. The patient developed clinically significant hypotension, despite transfusion of blood products. The heparin infusion was discontinued and the patient was converted to venoarterial ECLS via the right common carotid artery and internal jugular vein. Thoracostomy was performed with a 27F ArgyleTM catheter (Covidien, Mansfield, MA) tube and the heparin infusion was reinitiated. Suction drainage was continued for three weeks. However, persistent compressive atelectasis, poor pulmonary compliance, and failure to wean from ECLS after three weeks of support suggested the presence of a clinically significant retained hemothorax. We elected to lyse the organized hemothorax with intrapleural TPA to avoid the risk of traditional surgical drainage during ECLS. Recombinant human TPA (AlteplaseTM [Genentech, South San Francisco, CA] 2 mg in 10 mL of sterile normal saline) was instilled through the
1 Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA 2 Division of Cardiac Surgery, Seattle Children’s Hospital, Seattle, WA, USA 3 Division of Pediatric Critical Care, Seattle Children’s Hospital, Seattle, WA, USA
Corresponding Author: David Michael McMullan, 4800 Sand Point Way NE, M/S RC.2.280, Seattle, WA 98105, USA. Email: [email protected]
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
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World Journal for Pediatric and Congenital Heart Surgery 6(1)
Figure 1. Serial chest radiographs from patient 1 demonstrating improved lung aeration and decreased right pleural effusion after 72 hours of intrapleural tissue plasminogen activator (TPA) therapy.
existing pleural drain, which was then clamped for 12 hours. After removal of the clamp, intrapleural fluid was evacuated by gravity drainage. The TPA instillation process was repeated three times at 24-hour intervals. Heparin infusion was decreased to maintain the ACT between 160 and 180 seconds, and platelet transfusion was performed to achieve a platelet count >100,000 cells/mL during the period of fibrinolysis. During the 72 hours of fibrinolytic therapy, cumulative pleural drainage was 300 mL (15 mL/kg) and serial chest radiographs confirmed reduced volume of intrapleural hematoma and improved lung aeration (Figure 1). The patient exhibited increased pulmonary compliance and oxygenation and was successfully separated from ECLS four days after completion of TPA-mediated thrombolysis of the retained hemothorax. She was subsequently discharged from the hospital with preserved pulmonary function.
to surgical evacuation of retained hemothorax. Recombinant human TPA (AlteplaseTM 2 mg in 10 mL of sterile normal saline) was instilled through a newly placed percutaneous 8F apical pleural drain, and all drains were clamped for 1 hour. Intrapleural fluid was evacuated by gravity drainage after the removal of the clamps. This process was repeated at 24-hour intervals for three cycles during which the plural drainage increased from 100,000 cells/mL during the three-day period of fibrinolytic therapy. The patient was able to wean from ECLS two days after the first TPA treatment. Three additional cycles of intrapleural TPA were performed after separation from ECLS to address a small residual hemothorax. There were no hemorrhagic compilations. She was subsequently weaned from mechanical ventilatory support and discharged from the intensive care unit.
Patient 2 A three-year-old (14 kg) girl experienced refractory cardiovascular collapse due to gram-negative sepsis seven weeks after Fontan palliation of hypoplastic left heart syndrome. Failing to respond to standard cardiopulmonary resuscitation, she was emergently placed on venoarterial ECLS via the right common carotid artery and internal jugular vein. Systemic anticoagulation was achieved by continuous heparin infusion to maintain the ACT between 200 and 220 seconds. She underwent tube thoracostomy on the fifth day of ECLS to evacuate a large right pleural effusion. Although heparin was discontinued prior to the procedure, she developed intrathoracic bleeding. Control of chest wall and pleural hemorrhage was achieved by electrocautery via a small anterolateral thoracotomy incision. She developed a large retained hemothorax that impaired recovery of lung function and weaning from ECLS, despite placement of an additional 8F pleural pigtail catheter and ongoing suction drainage. Intrapleural fibrinolysis was performed on ECLS day 10 (60 days following the Fontan procedure) as an alternative
Discussion Intrathoracic complications, including hemothorax, pneumothorax, and pericardial tamponade, occur in approximately 10% of patients on ECLS.3 Although open and thoracoscopic evacuation are the standard approaches to managing retained hemothorax, relatively simple procedures, such as tube thoracostomy, may be risky when performed on ECLS patients.4 Intrapleural fibrinolysis of retained hemothorax has been safely used in non-ECLS adult patients with reported success rates of 67% to 92%,5 including patients undergoing concomitant systemic anticoagulation.6,7 There is little evidence that fibrinolytic therapy increases the risk of clinically significant hemorrhage in patients receiving systemic anticoagulation therapy.6,7 In addition systemically and locally administered TPA has been used for intra-arterial, intracardiac, and intravesicular thrombolysis in neonatal and pediatric ECLS patients. Neither of our patients experienced local or distant hemorrhagic complications related to intrapleural TPA administration.
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
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The dose of intrapleural TPA (2 mg), frequency of administration (every 24 hours), and duration of therapy (72 hours), for both patients were selected based on our institutional experience with fibrinolysis for pleural space infections and are consistent with dosing strategies from limited reports of intrapleural fibrinolysis for retained hemothorax in pediatric patients.7 Due to the paucity of pharmacological data for intrapleural TPA administration, optimal dwell times, systemic absorption, toxicity, and dosing have not been well established.8 When possible, it is our preference to delay open pleural drainage or decortication for retained hemothorax until after separation from ECLS. However, the physiological sequelae of retained hemothorax appeared to prevent effective weaning and separation from ECLS in our patients. Radiographic evidence of improved lung aeration and reduced volume of intrapleural blood was apparent within a few days of initiation of intrapleural fibrinolysis. Both patients successfully separated from ECLS and were extubated shortly after initiation of intrapleural TPA, despite protracted courses of ECLS. Intrapleural fibrinolysis appears to be a safe and efficacious therapeutic option for ECLS patients when employed in a stepwise manner between tube thoracostomy and surgical exploration. Infrequent use of TPA during ECLS precludes an accurate estimation of the true risk of hemorrhagic complications. However, it is clear that surgical alternatives to evacuate the pleural space can be associated with significant morbidity.2 Additional experience is needed to determine optimal drug dosing and anticoagulation management, true efficacy, and risk profile of this nonsurgical approach. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. 2014 ELSO International Summary. Extracorporeal Life Support Organization Registry. Ann Arbor, MI: ELSO;March 2014. 2. Atkinson JB, Kitagawa H, Humphries B. Major surgical intervention during extracorporeal membrane oxygenation. J Pediatr Surg. 1992;27(9): 1197-1198. 3. Zwischenberger JB, Cilley RE, Hirschl RB, Heiss KF, Conti VR, Bartlett RH. Life-threatening intrathoracic complications during treatment with extracorporeal membrane oxygenation. J Pediatr Surg. 1988;23(7): 599-604. 4. Jackson HT, Longshore S, Feldman J, Zirschky K, Gingalewski CA, Gollin G. Chest tube placement in children during extracorporeal membrane oxygenation (ECMO). J Pediatr Surg. 2014; 49(1): 51-53; discussion 53-54. 5. Kimbrell BJ, Yamzon J, Petrone P, Asensio JA, Velmahos GC. Intrapleural thrombolysis for the management of undrained traumatic hemothorax: a prospective observational study. J Trauma. 2007;62(5): 1175-8; discussion 1178-1179. 6. Ben-Or S, Feins RH, Veeramachaneni NK, Haithcock BE. Effectiveness and risks associated with intrapleural alteplase by means of tube thoracostomy. Ann Thorac Surg. 2011;91(3): 860-863; discussion 863-864. 7. Gervais DA, Levis DA, Hahn PF, Uppot RN, Arellano RS, Mueller PR. Adjunctive intrapleural tissue plasminogen activator administered via chest tubes placed with imaging guidance: effectiveness and risk for hemorrhage. Radiology. 2008;246(3): 956-963. 8. Heppler JS. Intrapleural fibrinolytics for pleural infection: optimizing dosing for future trials. Mayo Clin Proc. 2007;82(8): 1016; author reply 1016-1017.
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
Intrapleural Fibrinolysis During Pediatric Extracorporeal Life Support
World Journal for Pediatric and Congenital Heart Surgery 2015, Vol. 6(1) 123-125 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/2150135114553478 pch.sagepub.com
Cordelie E. Witt, MD1, Andrew L. Mesher, MD1, Joshua L. Hermsen, MD2, Thomas V. Brogan, MD3, and David Michael McMullan, MD1,2
Abstract Pediatric patients who require extracorporeal life support (ECLS) for refractory cardiorespiratory failure are at increased risk for intrapleural hemorrhage due to the effects of systemic anticoagulation and frequent occurrence of pneumothorax. Surgical evacuation is standard therapy for retained hemothorax to prevent secondary empyema, pulmonary compression, and development of fibrothorax. However, surgical interventions during ECLS are hazardous and place patients at increased risk for surgical site bleeding. Intrapleural fibrinolysis with tissue plasminogen activator may be used to facilitate nonsurgical evacuation of retained hemothorax. We present two pediatric patients who were safely and successfully managed with intrapleural fibrinolysis of retained hemothorax during ECLS. Keywords extracorporeal membrane oxygenation, hemothorax, pleural space, pediatric Submitted June 14, 2014; Accepted September 01, 2014.
Despite improvements in extracorporeal life support (ECLS) circuitry and anticoagulation strategies, up to 30% of highrisk neonates develop hemothorax during ECLS.1 When inadequately evacuated, retained hemothorax may prevent weaning from ECLS and increase the risk of empyema and fibrothorax. Surgical procedures, including thoracoscopic or open surgical drainage of retained intrathoracic blood, are associated with increased risk of hemorrhage and death in this population.2 Intrapleural fibrinolysis using tissue plasminogen activator (TPA) to promote breakdown and evacuation of retained hemothorax is an attractive alternative to surgical drainage in these high-risk patients. We present two patients who underwent successful intrapleural TPA-mediated thrombolysis of retained hemothoraxes during ECLS
Case Reports Patient 1 A previously healthy four-year-old (20 kg) girl was admitted to the intensive care unit for severe respiratory distress due to Streptococcus pneumoniae and human metapneumovirus pneumonia. She was placed on venovenous ECLS via the right internal jugular vein and received systemic anticoagulation by continuous heparin infusion to maintain an activated clotting time (ACT) of 200 to 220 seconds. On the 11th day of ECLS, she developed a large hemothorax after insertion of a small-
bore chest drain to evacuate a spontaneous right pneumothorax. The patient developed clinically significant hypotension, despite transfusion of blood products. The heparin infusion was discontinued and the patient was converted to venoarterial ECLS via the right common carotid artery and internal jugular vein. Thoracostomy was performed with a 27F ArgyleTM catheter (Covidien, Mansfield, MA) tube and the heparin infusion was reinitiated. Suction drainage was continued for three weeks. However, persistent compressive atelectasis, poor pulmonary compliance, and failure to wean from ECLS after three weeks of support suggested the presence of a clinically significant retained hemothorax. We elected to lyse the organized hemothorax with intrapleural TPA to avoid the risk of traditional surgical drainage during ECLS. Recombinant human TPA (AlteplaseTM [Genentech, South San Francisco, CA] 2 mg in 10 mL of sterile normal saline) was instilled through the
1 Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA 2 Division of Cardiac Surgery, Seattle Children’s Hospital, Seattle, WA, USA 3 Division of Pediatric Critical Care, Seattle Children’s Hospital, Seattle, WA, USA
Corresponding Author: David Michael McMullan, 4800 Sand Point Way NE, M/S RC.2.280, Seattle, WA 98105, USA. Email: [email protected]
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
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World Journal for Pediatric and Congenital Heart Surgery 6(1)
Figure 1. Serial chest radiographs from patient 1 demonstrating improved lung aeration and decreased right pleural effusion after 72 hours of intrapleural tissue plasminogen activator (TPA) therapy.
existing pleural drain, which was then clamped for 12 hours. After removal of the clamp, intrapleural fluid was evacuated by gravity drainage. The TPA instillation process was repeated three times at 24-hour intervals. Heparin infusion was decreased to maintain the ACT between 160 and 180 seconds, and platelet transfusion was performed to achieve a platelet count >100,000 cells/mL during the period of fibrinolysis. During the 72 hours of fibrinolytic therapy, cumulative pleural drainage was 300 mL (15 mL/kg) and serial chest radiographs confirmed reduced volume of intrapleural hematoma and improved lung aeration (Figure 1). The patient exhibited increased pulmonary compliance and oxygenation and was successfully separated from ECLS four days after completion of TPA-mediated thrombolysis of the retained hemothorax. She was subsequently discharged from the hospital with preserved pulmonary function.
to surgical evacuation of retained hemothorax. Recombinant human TPA (AlteplaseTM 2 mg in 10 mL of sterile normal saline) was instilled through a newly placed percutaneous 8F apical pleural drain, and all drains were clamped for 1 hour. Intrapleural fluid was evacuated by gravity drainage after the removal of the clamps. This process was repeated at 24-hour intervals for three cycles during which the plural drainage increased from 100,000 cells/mL during the three-day period of fibrinolytic therapy. The patient was able to wean from ECLS two days after the first TPA treatment. Three additional cycles of intrapleural TPA were performed after separation from ECLS to address a small residual hemothorax. There were no hemorrhagic compilations. She was subsequently weaned from mechanical ventilatory support and discharged from the intensive care unit.
Patient 2 A three-year-old (14 kg) girl experienced refractory cardiovascular collapse due to gram-negative sepsis seven weeks after Fontan palliation of hypoplastic left heart syndrome. Failing to respond to standard cardiopulmonary resuscitation, she was emergently placed on venoarterial ECLS via the right common carotid artery and internal jugular vein. Systemic anticoagulation was achieved by continuous heparin infusion to maintain the ACT between 200 and 220 seconds. She underwent tube thoracostomy on the fifth day of ECLS to evacuate a large right pleural effusion. Although heparin was discontinued prior to the procedure, she developed intrathoracic bleeding. Control of chest wall and pleural hemorrhage was achieved by electrocautery via a small anterolateral thoracotomy incision. She developed a large retained hemothorax that impaired recovery of lung function and weaning from ECLS, despite placement of an additional 8F pleural pigtail catheter and ongoing suction drainage. Intrapleural fibrinolysis was performed on ECLS day 10 (60 days following the Fontan procedure) as an alternative
Discussion Intrathoracic complications, including hemothorax, pneumothorax, and pericardial tamponade, occur in approximately 10% of patients on ECLS.3 Although open and thoracoscopic evacuation are the standard approaches to managing retained hemothorax, relatively simple procedures, such as tube thoracostomy, may be risky when performed on ECLS patients.4 Intrapleural fibrinolysis of retained hemothorax has been safely used in non-ECLS adult patients with reported success rates of 67% to 92%,5 including patients undergoing concomitant systemic anticoagulation.6,7 There is little evidence that fibrinolytic therapy increases the risk of clinically significant hemorrhage in patients receiving systemic anticoagulation therapy.6,7 In addition systemically and locally administered TPA has been used for intra-arterial, intracardiac, and intravesicular thrombolysis in neonatal and pediatric ECLS patients. Neither of our patients experienced local or distant hemorrhagic complications related to intrapleural TPA administration.
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
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The dose of intrapleural TPA (2 mg), frequency of administration (every 24 hours), and duration of therapy (72 hours), for both patients were selected based on our institutional experience with fibrinolysis for pleural space infections and are consistent with dosing strategies from limited reports of intrapleural fibrinolysis for retained hemothorax in pediatric patients.7 Due to the paucity of pharmacological data for intrapleural TPA administration, optimal dwell times, systemic absorption, toxicity, and dosing have not been well established.8 When possible, it is our preference to delay open pleural drainage or decortication for retained hemothorax until after separation from ECLS. However, the physiological sequelae of retained hemothorax appeared to prevent effective weaning and separation from ECLS in our patients. Radiographic evidence of improved lung aeration and reduced volume of intrapleural blood was apparent within a few days of initiation of intrapleural fibrinolysis. Both patients successfully separated from ECLS and were extubated shortly after initiation of intrapleural TPA, despite protracted courses of ECLS. Intrapleural fibrinolysis appears to be a safe and efficacious therapeutic option for ECLS patients when employed in a stepwise manner between tube thoracostomy and surgical exploration. Infrequent use of TPA during ECLS precludes an accurate estimation of the true risk of hemorrhagic complications. However, it is clear that surgical alternatives to evacuate the pleural space can be associated with significant morbidity.2 Additional experience is needed to determine optimal drug dosing and anticoagulation management, true efficacy, and risk profile of this nonsurgical approach. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. 2014 ELSO International Summary. Extracorporeal Life Support Organization Registry. Ann Arbor, MI: ELSO;March 2014. 2. Atkinson JB, Kitagawa H, Humphries B. Major surgical intervention during extracorporeal membrane oxygenation. J Pediatr Surg. 1992;27(9): 1197-1198. 3. Zwischenberger JB, Cilley RE, Hirschl RB, Heiss KF, Conti VR, Bartlett RH. Life-threatening intrathoracic complications during treatment with extracorporeal membrane oxygenation. J Pediatr Surg. 1988;23(7): 599-604. 4. Jackson HT, Longshore S, Feldman J, Zirschky K, Gingalewski CA, Gollin G. Chest tube placement in children during extracorporeal membrane oxygenation (ECMO). J Pediatr Surg. 2014; 49(1): 51-53; discussion 53-54. 5. Kimbrell BJ, Yamzon J, Petrone P, Asensio JA, Velmahos GC. Intrapleural thrombolysis for the management of undrained traumatic hemothorax: a prospective observational study. J Trauma. 2007;62(5): 1175-8; discussion 1178-1179. 6. Ben-Or S, Feins RH, Veeramachaneni NK, Haithcock BE. Effectiveness and risks associated with intrapleural alteplase by means of tube thoracostomy. Ann Thorac Surg. 2011;91(3): 860-863; discussion 863-864. 7. Gervais DA, Levis DA, Hahn PF, Uppot RN, Arellano RS, Mueller PR. Adjunctive intrapleural tissue plasminogen activator administered via chest tubes placed with imaging guidance: effectiveness and risk for hemorrhage. Radiology. 2008;246(3): 956-963. 8. Heppler JS. Intrapleural fibrinolytics for pleural infection: optimizing dosing for future trials. Mayo Clin Proc. 2007;82(8): 1016; author reply 1016-1017.
Downloaded from pch.sagepub.com at UNIV OF CONNECTICUT on June 9, 2015
