Pushing tPA in a code situation: what’s the evidence / when can we make the most difference?

Authors: Deepak Sekaran, MD, Anthony Scoccimarro, MD and Muhammad Waseem, MD, MS (Lincoln Medical & Mental Health Center, Bronx New York) // Edited by: Jennifer Robertson, MD and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital)

BACKGROUND

Cardiac arrest is a problem that is seen frequently in emergency departments. Estimates show that 155,000 patients have an out-of-hospital cardiac arrest annually, with a survival rate of less than 10%. 70% of these cases are caused by myocardial infarction and pulmonary embolism (PE).1 Given the pro-thrombotic state caused by both of these pathologies, the use of a thrombolytic drug seems to be a reasonable choice in the coding patient.2 However, thrombolytic medications should always be administered with caution because of the high risk of bleeding.  While there is some evidence to justify their administration to patients with a ST elevation MI (STEMI) or unstable patients with PE, the data from code situations with ongoing cardiopulmonary resuscitation (CPR) is limited.

CARDIAC ARREST AND PE

The general incidence of PE without cardiac arrest is 1 in 1000 annually, with a mortality rate of up to 17% in the first 3 months. Cardiac arrest in the context of PE usually results from right ventricular (RV) obstruction leading to increased oxygen demand, decreased left ventricular (LV) filling and ischemia.3 Patients usually present in pulseless electrical activity (PEA), with a mortality ranging from 65 to 95 percent 4. Bedside ultrasound has been demonstrated to be a useful adjunct in the evaluation of reversible causes of cardiac arrest, including PE.4 Sonographic findings suggestive of PE including intraventricular thrombus,  RV dilatation (RV/LV > 1:1), septal bowing, and RV hypokinesis with normal apical contractility (McConnell sign).5,6 In a joint statement from the American College of Emergency Physicians (ACEP) and the American College of Echocardiography, focused cardiac ultrasound is beneficial in patients with suspected PE in order to prioritize further testing. Focused echocardiography is also useful in determining differential diagnoses and treatment decisions in severely compromised patients.7  Fibrinolysis is currently recommended for confirmed pulmonary embolism complicated by hemodynamic instability, or severe RV dysfunction.8 The outcomes for clinically stable pulmonary embolism show a notably lower mortality rate (5%), where the need for thrombolytic is uncertain.9

CARDIAC ARREST AND MI

In STEMI patients without cardiac arrest, reperfusion therapy has shown a benefit in preserving LV function and minimizing damage. However, this therapy in patients with non-STEMI has not been proven beneficial. Theoretically, a cardiac arrest with a thrombotic origin would benefit from fibrinolysis, but in practice it is not easy to differentiate among the specific types of MI in the context of cardiac arrest.10 Current guidelines recommend considering TPA in patients with cardiac arrest from pulmonary embolism; but cite insufficient data to make a recommendation for its role in cardiac arrest from myocardial infarction.11

DOES FIBRINOLYSIS IMPROVE NEUROLOGICAL OUTCOME?

Although the pressing concern in a cardiac arrest is the return of spontaneous circulation  (ROSC) and addressing the inciting factor, the long term outcome will largely be determined by the amount of cerebral hypoxia during the code. There are several proposed mechanisms for neuronal cell death secondary to coagulopathy, including micro-thrombi formed from poor circulation and also an overall pro-thrombotic state caused by the inflammatory response and the occurrence of free oxygen radicals. Blood samples taken during CPR and up to 72 hours following the restoration of circulation have shown increased coagulation not counteracted by endogenous fibrinolysis12. This information supports the theory that thrombolysis can be beneficial by preventing microvascular ischemia. This was tested in a study of cats who were subjected to cardiac arrest followed by CPR, with one cohort receiving TPA. The subjects who were given thrombolytic showed a decreased cerebral ischemia.13

WILL CPR + TPA KILL MY PATIENT?

In both American and European guidelines, CPR is currently listed as a relative contraindication for fibrinolysis. This was based on the meta-analysis of patients with myocardial infarction who received fibrinolytics.14 While the results showed a three-fold increase in severe bleeding compared to patients who did not receive reperfusion, there were no data on patients who were actively receiving CPR. Thus, the relationship between prolonged chest compressions and bleeding risk remains unclear. Retrospective trials were performed in the early 1990s to compare outcomes of patients admitted with successful resuscitation following out-of-hospital cardiac arrest.15 The cohort receiving fibrinolysis showed the expected two-fold increased risk of increased bleeding, but the data were insufficient to reach a conclusion regarding long term survival. Interestingly, none of the bleeding episodes resulted in death, and there were no risks of increased bleeding pursuant to prolonged CPR. A similar study was performed on cardiac arrest patients with known diagnosis of PE showing the expected two-fold risk of bleeding, but also an improvement in survival and no association between prolonged CPR and increased bleeding.16

HAVE ANY STUDIES ADDRESSED THIS QUESTION DIRECTLY?

The Thrombolysis in Cardiac Arrest (TROICA) trial was the first large scale multicenter prospective placebo-controlled double blind trial, enrolling patients with witnessed out-of-hospital cardiac arrest of presumed cardiac origin, notably excluding patients with known diagnosis of PE. The data showed no significant difference in efficacy end points, including ROSC, admission, 24-hour survival, survival to discharge and neurologic outcome. However, the study’s authors remain optimistic about the utility of TPA in a cardiac code. They claim that outcomes may be improved if combined with heparin, given that global coagulation occurs with cardiac arrest.2

BOTTOM LINE

In a code situation, a fibrinolytic can theoretically be given to remove the causative factor and reduce microvascular ischemia. A two-fold risk in bleeding should be expected.

Although CPR is currently listed as a relative contraindication for TPA, prior studies do not appear to show a correlation between prolonged CPR and increased bleeding following the administration of fibrinolytic.

One should always consider bedside ultrasound as a diagnostic adjunct in cardiac arrest.

Evidence and guidelines recommend administering fibrinolytic to any unstable patient with PE, which includes patients in cardiac arrest.

Administering a thrombolytic in a cardiac arrest from MI remains controversial. The benefits may outweigh the bleeding risks in the context of a STEMI. However, obtaining this diagnosis in a code situation is difficult. Empiric administration may lead to adverse outcomes if there is a non-thrombotic cause of arrest. Until further evidence is obtained, each event should be considered on an individual case by case basis.

References/Further Reading

  1. Silfvast T. Cause of death in unsuccessful prehospital resuscitation. J Intern Med1991;229:331-335
  2. Bottiger BW, Martin E. Thrombolytic therapy during cardiopulmonary resuscitation and the role of coagulation activation after cardiac arrest. Curr Opin Crit Care 2001;7: 176-183
  3. Brembilla-Perrot B1,Miljoen H,Houriez PBeurrier DNippert MVançon ACde la Chaise ATLouis PMock LSadoul NAndronache M. Causes and prognosis of cardiac arrest in a population admitted to a general hospital; a diagnostic and therapeutic problem. Resuscitation 2003;58:319-327
  4. Hernandez C1,Shuler KHannan HSonyika CLikourezos AMarshall J.”CAUSE: cardiac arrest ultra-sound exam—a better approach to managing patients in primary non-arrhythmogenic cardiac arrest.” Resuscitation 76.2 (2008): 198-206
  5. Borloz MP, Frohna WJ, Phillips CA, Antonis MS. “Emergency department focused bedside echocardiography in massive pulmonary embolism.”The Journal of emergency medicine41.6 (2011): 658-660
  6. Patel AN, Nickels LC, Flach FE, De Portu G, Ganti L. The Use of Bedside Ultrasound in the Evaluation of Patients Presenting with Signs and Symptoms of Pulmonary Embolism.Case reports in emergency medicine 2013;2013:312632
  7. Labovitz AJ, Noble VE, Bierig M, Goldstein SA, Jones R, Kort S, Porter TR, Spencer KT, Tayal VS, Wei K. “Focused cardiac ultrasound in the emergent setting: a consensus statement of the American Society of Echocardiography and American College of Emergency Physicians.”Journal of the American Society of Echocardiography 23.12 (2010): 1225-1230
  8. Bailén MR, Cuadra JA, Aguayo De Hoyos E. Thrombolysis during cardiopulmonary resuscitation in fulminant pulmonary embolism: a review. Crit Care Med 2001;29:2211-2219
  9. Goldhaber SZ, Elliott CG. Acute pulmonary embolism. Part II: risk stratification, treatment, and prevention. Circulation 2003;108:2834-2838
  10. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB trial. Thrombolysis in myocardial ischemia. Circulation 1994;89(4):1545-1556
  11. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112:Suppl:IV1-IV203
  12. Böttiger BW, Motsch J, Böhrer H, Böker T, Aulmann M, Nawroth PP, Martin E.Activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Circulation 1995;92:2572-2578
  13. Fischer M, Bottiger BW, Popov-Cenic S, Hossmann KA. Thrombolysis using plasminogen activator and heparin reduces cerebral no-reflow after resuscitation from cardiac arrest: an experimental study in the cat. Intensive Care Med 1996;22:1214-1223
  14. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Ornato JP. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:E1-211
  15. Scholz KH, Tebbe U, Herrmann C, Wojcik J, Lingen R, Chemnitius JM, Brune S, Kreuzer H. Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction. Am J Cardiol 1992;69:724-728
  16. Janata K,Holzer M,Kürkciyan ILosert HRiedmüller EPikula BLaggner ANLaczika K.. Major bleeding complications in cardiopulmonary resuscitation: the place of thrombolytic therapy in cardiac arrest due to massive pulmonary embolism. Resuscitation 2003;57:49-55

 

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