Thrombolytics for pulmonary embolism: Difference between revisions

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==Indications==
==Indications==
*Patients with [[Pulmonary_embolism#Massive:_High-risk|massive PE]] (i.e. persistent hypotension SBP <90 for ≥15 mins or requiring inotropic support) and acceptable risk of bleeding complications<ref>ACCP 9th Edition of the Antithrombotic Therapy Guidelines: Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2012;141:e419s – e494s. doi: 10.1378/chest.11-2301.</ref>
*Patients with [[Pulmonary_embolism#Massive:_High-risk|massive PE]] (i.e. persistent [[hypotension]] SBP <90 for ≥15 mins or requiring inotropic support) and acceptable risk of bleeding complications<ref>ACCP 9th Edition of the Antithrombotic Therapy Guidelines: Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2012;141:e419s – e494s. doi: 10.1378/chest.11-2301.</ref>
*Can be considered in initially hemodynamically stable patients (i.e. submassive PE) who acutely decompensate despite anticoagulation
*Can be considered in initially hemodynamically stable patients (i.e. submassive PE) who acutely decompensate despite anticoagulation
**develop persistent hypotension (massive PE)
**develop persistent [[hypotension]] (massive PE)
**increasing heart rate
**increasing [[tachycardia|heart rate]]
**JVD or worsening right heart failure
**JVD or worsening right [[heart failure]]
**worsening gas exchange
**worsening gas exchange
**signs of shock
**signs of [[shock]]


===Evaluation===
===Evaluation===
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*'''Massive PE'''<ref>Circulation 2011;123:1788</ref>
*'''Massive PE'''<ref>Circulation 2011;123:1788</ref>
**Acute with  
**Acute with  
***Sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular [LV] dysfunction)
***Sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular [LV] dysfunction) - ACCP 2016
***Pulselessness
***Other definitions include pulselessness or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock)
***Or, persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock)
*'''Submassive PE'''<ref>Circulation 2011;123:1788</ref>
*'''Submassive PE'''<ref>Circulation 2011;123:1788</ref>
**Acute without systemic hypotension (see above) but with either RV dysfunction or myocardial necrosis
**Acute without systemic hypotension (see above) but with either RV dysfunction or myocardial necrosis
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****Elevation of BNP (>90 pg/mL)
****Elevation of BNP (>90 pg/mL)
****Elevation of N-terminal pro-BNP (>500 pg/mL); or
****Elevation of N-terminal pro-BNP (>500 pg/mL); or
***Electrocardiographic changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
***[[EKG|Electrocardiographic]] changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
***Myocardial necrosis is defined as either of the following:
***Myocardial necrosis is defined as either of the following:
****Elevation of troponin I (>0.4 ng/mL) or
****Elevation of troponin I (>0.4 ng/mL) or
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===Absolute contraindications===
===Absolute contraindications===
*Any prior [[intracranial hemorrhage]]
*Any prior [[intracranial hemorrhage]]
*Known structural intracranial cerebrovascular disease (e.g. AVM)
*Known structural intracranial cerebrovascular disease (e.g. [[AVM]])
*Known malignant intracranial neoplasm
*Known malignant [[brain tumor|intracranial neoplasm]]
*Ischemic stroke within last 3 months
*[[Ischemic stroke]] within last 3 months
*Suspected aortic dissection
*Suspected [[aortic dissection]]
*Active bleeding or bleeding diathesis
*Active [[hemorrhage|bleeding]] or [[coagulopathy|bleeding diathesis]]
*Recent surgery encroaching on the spinal canal or brain
*Recent surgery encroaching on the spinal canal or brain
*Recent closed-head or [[facial trauma]] with radiographic evidence of bony fracture or brain injury
*Recent closed-[[head trauma|head]] or [[facial trauma]] with radiographic evidence of bony [[facial fracture|fracture]] or brain injury


===Relative contraindications===
===Relative contraindications===
*Age >75 years
*Age >75 years
*Current use of anticoagulation
*Current use of [[anticoagulation]]
*[[PE in Pregnancy]]
*[[PE in Pregnancy]]
*Noncompressible vascular punctures
*Noncompressible vascular punctures
*Traumatic or prolonged [[CPR]] (>10min)
*Traumatic or prolonged [[CPR]] (>10min)
*Recent internal bleeding (within 2 to 4 weeks)
*Recent internal bleeding (within 2 to 4 weeks)
*History of chronic, severe, and poorly controlled hypertension
*History of chronic, severe, and poorly controlled [[hypertension]]
*Severe uncontrolled hypertension on presentation (sys BP >180 or dia BP >110)
*Severe uncontrolled [[hypertension]] on presentation (sys BP >180 or dia BP >110)
*Dementia
*[[Dementia]]
*Remote (>3 months) ischemic stroke
*Remote (>3 months) [[ischemic stroke]]
*Major surgery within 3 weeks
*Major surgery within 3 weeks


==Administration==
==Administration==
''Administration regimens differ widely in the literature, options not in any particular order, include:''
*Standard dose: [[Alteplase]] 100mg over 2 hours <ref>Martin C et al. Systemic thrombolysis for pulmonary embolism: a review. P T. 2016 Dec; 41(12):770-775.</ref><ref>Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11026</ref>
*[[Alteplase]] 0.6 - 1 mg/kg or 100 mg with any of the three possibilities
*Alternative dose: [[Alteplase]] 50mg over 2 hours
**Two 50 mg boluses, 30 min apart<ref>Kürkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-1535.</ref><ref>Ruiz-Bailén M, Aguayo-de-Hoyos E, Serrano-Córcoles M, et al. Thrombolysis with recombinant tissue plasminogen activator during cardiopulmonary resuscitation in fulminant pulmonary embolism. A case series. Resuscitation. 2001;51(1):97-101.</ref>
**Half-dose regimen can be considered in patients >65yo, higher bleeding risk, or submassive PE (see [[EBQ:MOPETT_Trial| MOPETT trial]])
**15 mg bolus, followed by 85 mg over 90 min<ref> Kürkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-1535.</ref>
*Systemic therapy is recommended over catheter-directed therapy
**100 mg over 15 min<ref>Abu-Laban R, Christenson J, Innes G, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med. 2002;346(20):1522-1528.</ref>
*Cardiac arrest dose:<ref>Scott Weingart. EMCrit 261 – Thrombolysis during Cardiac Arrest. EMCrit Blog. Published on December 12, 2019. Accessed on December 13th 2019. Available at https://emcrit.org/emcrit/thrombolysis-cardiac-arrest/ </ref>
*[[Tenecteplase]] in at 50 mg bolus or 0.5 mg/kg bolus <ref>Fatovich D, Dobb G, Clugston R. A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation. 2004;61(3):309-313.</ref><ref>Bozeman W, Kleiner D, Ferguson K. Empiric tenecteplase is associated with increased return of spontaneous circulation and short term survival in cardiac arrest patients unresponsive to standard interventions. Resuscitation. 2006;69(3):399-406.</ref><ref>Böttiger B, Arntz H, Chamberlain D, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25):2651-2662.</ref>
**[[Tenecteplase]] (not FDA approved for PE) - 50 mg bolus or 0.5 mg/kg bolus has been used for PEA arrest
<ref>Fatovich D, Dobb G, Clugston R. A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation. 2004;61(3):309-313.</ref><ref>Bozeman W, Kleiner D, Ferguson K. Empiric tenecteplase is associated with increased return of spontaneous circulation and short term survival in cardiac arrest patients unresponsive to standard interventions. Resuscitation. 2006;69(3):399-406.</ref><ref>Böttiger B, Arntz H, Chamberlain D, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25):2651-2662.</ref>'''OR'''
**[[Alteplase]] - 50 mg of  by IV Push over ~60 seconds
**Continue CPR for 30-60 minutes after lytic administration.


===Related Instructions===
===Related Instructions===
*Review contraindications (below)
*Review [[Thrombolytics_for_pulmonary_embolism#Contraindications| contraindications]]
*After infusion complete measure serial aPTTs
*Several trials continued unfractionated heparin (UFH) to target aPTT 1.5-2.5x baseline during thrombolytic administration so this would be standard <ref>Konstantinides S et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002 Oct 10;347(15):1143-50.</ref><ref>Meyer G et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.</ref>
**Almost all studies of thrombolysis administration included heparin anticoagulation
**However, discontinuing anticoagulation can be considered while administering thrombolytics
**Once value is <2x upper limit restart anticoagulation
*Always obtain serial aPTT every 4 hours after completion of thrombolytic
*Ongoing CPR from 2010 AHA Guidelines is not an absolute contraindication, and some studies suggest permiting 15 min of CPR to allow thrombolysis to work<ref>Hayes BD. What’s the Code Dose of tPA? Updated August 2016. https://www.aliem.com/2013/whats-code-dose-of-tpa/.</ref>
**If heparin was discontinued during thrombolysis, resume heparin without a loading dose when aPTT <2x upper limit of normal
*Discontinue heparin during infusion
*Ongoing CPR from 2010 AHA Guidelines is not an absolute contraindication, and some studies suggest permitting 15 min of CPR to allow thrombolysis to work<ref>Hayes BD. What’s the Code Dose of tPA? Updated August 2016. https://www.aliem.com/2013/whats-code-dose-of-tpa/.</ref>


==Complications==
==Complications==
*Major bleeding<ref>Chatterjee S et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990.</ref>
**Major bleeding OR 2.73 (9.24% vs 3.42%) compared to anticoagulant alone
**[[Intracranial hemorrhage]] OR 4.63 (1.46% vs 0.19%)
**'''There was no statistically significant increase in major bleeding risk in patients 65yo or younger'''
*No standard or evidence-based reversal regimen exists but general guidelines include: <ref> Yaghi S, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplace in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the AHA/ASA. Stroke. 2017;48:e343–e361</ref>
**Supportive care (e.g. [[transfusion]])
**[[Cryoprecipitate]] (contains fibrinogen) 10 units or more to achieve fibrinogen level >150 mg/dL
**[[TXA]] or aminocaproic acid are antifibrinolytics, but limited data
**[[PCC]] or [[FFP]] can be considered, but generally as adjuncts to cryoprecipitate
**Consider [[vitamin K]]
**[[Platelets]] controversial (theoretical benefit, but a small study showed worsening ICH with platelets)
**Consider neurosurgical intervention if large ICH is found on CT


==See Also==
==See Also==
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==External Links==
==External Links==
*Example of decision making guide factoring in size of PE and lytics contraindications: https://emcrit.org/ibcc/pe/#algorithm
*http://emcrit.org/emcrit/aha-pulmonary-embolism-guidelines-2011/
*http://emcrit.org/emcrit/aha-pulmonary-embolism-guidelines-2011/


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[[Category:Procedures]]
[[Category:Procedures]]
[[Category:Pharmacology]]
[[Category:Pharmacology]]
[[Category:Critical Care]]

Revision as of 22:41, 3 November 2020

Overview

  • For most hemodynamically stable patients, thrombolytic therapy is NOT indicated
  • Major controversy exists regarding thrombolytic therapy in submassive PE. [1][2][3] The mortality benefit may be greatest in patients with right ventricular dysfunction. [4]
  • Bleeding risk is increased with increasing age especially in the group ≥ 65 yo[5]
  • There is no evidence suggesting administering thrombolytics within a certain window of time improves outcomes [6]
  • There is no evidence suggesting administering thrombolytics empirically during cardiac arrest improves outcomes
    • In patients with PEA secondary to confirmed PE, administration of thrombolytics may be indicated[7]

Indications

  • Patients with massive PE (i.e. persistent hypotension SBP <90 for ≥15 mins or requiring inotropic support) and acceptable risk of bleeding complications[8]
  • Can be considered in initially hemodynamically stable patients (i.e. submassive PE) who acutely decompensate despite anticoagulation

Evaluation

  • See Pulmonary Embolism (PE)
  • Massive PE[9]
    • Acute with
      • Sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular [LV] dysfunction) - ACCP 2016
      • Other definitions include pulselessness or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock)
  • Submassive PE[10]
    • Acute without systemic hypotension (see above) but with either RV dysfunction or myocardial necrosis
      • RV dysfunction means the presence of at least 1 of the following:
        • RV dilation (apical 4-chamber RV diameter divided by LV diameter >0.9) or RV systolic dysfunction on echocardiography
        • RV dilation (4-chamber RV diameter divided by LV diameter >0.9) on CT
        • Elevation of BNP (>90 pg/mL)
        • Elevation of N-terminal pro-BNP (>500 pg/mL); or
      • Electrocardiographic changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
      • Myocardial necrosis is defined as either of the following:
        • Elevation of troponin I (>0.4 ng/mL) or
        • Elevation of troponin T (>0.1 ng/mL)

Contraindications

Absolute contraindications

Relative contraindications

Administration

  • Standard dose: Alteplase 100mg over 2 hours [11][12]
  • Alternative dose: Alteplase 50mg over 2 hours
    • Half-dose regimen can be considered in patients >65yo, higher bleeding risk, or submassive PE (see MOPETT trial)
  • Systemic therapy is recommended over catheter-directed therapy
  • Cardiac arrest dose:[13]
    • Tenecteplase (not FDA approved for PE) - 50 mg bolus or 0.5 mg/kg bolus has been used for PEA arrest

[14][15][16]OR

    • Alteplase - 50 mg of by IV Push over ~60 seconds
    • Continue CPR for 30-60 minutes after lytic administration.

Related Instructions

  • Review contraindications
  • Several trials continued unfractionated heparin (UFH) to target aPTT 1.5-2.5x baseline during thrombolytic administration so this would be standard [17][18]
    • However, discontinuing anticoagulation can be considered while administering thrombolytics
  • Always obtain serial aPTT every 4 hours after completion of thrombolytic
    • If heparin was discontinued during thrombolysis, resume heparin without a loading dose when aPTT <2x upper limit of normal
  • Ongoing CPR from 2010 AHA Guidelines is not an absolute contraindication, and some studies suggest permitting 15 min of CPR to allow thrombolysis to work[19]

Complications

  • Major bleeding[20]
    • Major bleeding OR 2.73 (9.24% vs 3.42%) compared to anticoagulant alone
    • Intracranial hemorrhage OR 4.63 (1.46% vs 0.19%)
    • There was no statistically significant increase in major bleeding risk in patients 65yo or younger
  • No standard or evidence-based reversal regimen exists but general guidelines include: [21]
    • Supportive care (e.g. transfusion)
    • Cryoprecipitate (contains fibrinogen) 10 units or more to achieve fibrinogen level >150 mg/dL
    • TXA or aminocaproic acid are antifibrinolytics, but limited data
    • PCC or FFP can be considered, but generally as adjuncts to cryoprecipitate
    • Consider vitamin K
    • Platelets controversial (theoretical benefit, but a small study showed worsening ICH with platelets)
    • Consider neurosurgical intervention if large ICH is found on CT

See Also

Thrombolytics for pulmonary embolism

External Links

References

  1. Elliott C. et al. Fibrinolysis of Pulmonary Emboli — Steer Closer to Scylla.
  2. Sharifi M et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPPETT trial). J Cardiol 2013; 111: 273-7
  3. Meyer G. Fibrinolysis for patients with intermediate-risk pulmonary embolism. NEJM 2014; 370(15): 1402-1411
  4. Chatterjee. S et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014; 311(23):2414-21. PubMed ID: 24938564.
  5. EBQ:Thrombolysis_in_Pulmonary_Embolism_Metanalysis#Outcomes
  6. Daniels L et al. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Am J Cardiol. 1997 Jul 15;80(2):184-8
  7. 15. Sharifi M et al. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the “PEAPETT” study). Am J Emerg Med. 2016 Oct;34(10):1963-1967. doi: 10.1016/j.ajem.2016.06.094
  8. ACCP 9th Edition of the Antithrombotic Therapy Guidelines: Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2012;141:e419s – e494s. doi: 10.1378/chest.11-2301.
  9. Circulation 2011;123:1788
  10. Circulation 2011;123:1788
  11. Martin C et al. Systemic thrombolysis for pulmonary embolism: a review. P T. 2016 Dec; 41(12):770-775.
  12. Kearon C et al. Antithrombotic therapy for VTE disease. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11026
  13. Scott Weingart. EMCrit 261 – Thrombolysis during Cardiac Arrest. EMCrit Blog. Published on December 12, 2019. Accessed on December 13th 2019. Available at https://emcrit.org/emcrit/thrombolysis-cardiac-arrest/
  14. Fatovich D, Dobb G, Clugston R. A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation. 2004;61(3):309-313.
  15. Bozeman W, Kleiner D, Ferguson K. Empiric tenecteplase is associated with increased return of spontaneous circulation and short term survival in cardiac arrest patients unresponsive to standard interventions. Resuscitation. 2006;69(3):399-406.
  16. Böttiger B, Arntz H, Chamberlain D, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25):2651-2662.
  17. Konstantinides S et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002 Oct 10;347(15):1143-50.
  18. Meyer G et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
  19. Hayes BD. What’s the Code Dose of tPA? Updated August 2016. https://www.aliem.com/2013/whats-code-dose-of-tpa/.
  20. Chatterjee S et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990.
  21. Yaghi S, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplace in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the AHA/ASA. Stroke. 2017;48:e343–e361