Tenecteplase and return of spontaneous circulation after refractory cardiopulmonary arrest.

Abstract: Even with the benefit of cardiopulmonary resuscitation, the prognosis of cardiac arrest remains poor. Multiple case series describe survival with the use of thrombolytic therapy for refractory cardiac arrest. Presumably thrombolysis treats that subset of cardiac arrest cases resulting from fulminant pulmonary embolism, or perhaps massive myocardial infarctions. Published reports to date have dealt exclusively with streptokinase, urokinase, reteplase, or recombinant tissue plasminogen activator. The authors report the first case of return of spontaneous circulation with the administration of tenecteplase. Tenecteplase is a recently developed reengineered isomer of tissue plasminogen activator that possesses many properties of the ideal cardiac arrest thrombolytic agent. It is bolus dosed, stable at room temperature before reconstitution, and is compatible with most other advanced cardiac life support medications. Because of clinical equivalency and its logistical advantages, tenecteplase should be evaluated as an alternative to other thrombolytics in future trials involving cardiac arrest.

Key Words: cardiac arrest, pulmonary embolism, tenecteplase, thrombolysis

**********

Cardiac arrest occurs commonly, with almost 500,000 events in the United States annually. (1) Pulmonary embolism causes about 5 to 10% of all cardiac arrests, (2) and up to 50% of arrests manifesting electromechanical dissociation. (3) Therefore, a significant proportion of refractory cardiac arrest is caused by fulminant pulmonary embolism and might only respond to thrombolytic therapy. Initial evidence for the efficacy of thrombolysis in refractory cardiac arrest was limited to case series and review articles. Selectively published case series reported rates of return of spontaneous circulation (ROSC) after thrombolytic therapy of up to 50%. (4-6) However, more recent randomized trials failed to show long-term survival benefit with this therapy, (7,8) so research efforts continue.

The best choice for thrombolysis during cardiac arrest is unknown. The earliest published reports of thrombolysis in cardiac arrest were with urokinase and streptokinase. (6) More recent studies employed recombinant tissue plasminogen activator (tPA). (7,8) Tenecteplase (TNK), a recently developed reengineered isomer of tPA, is indicated for acute myocardial infarction. (9,10) It possesses many of the ideal properties for a thrombolytic agent (Table 1) and is compatible with most other advanced cardiac life support medications (except for dextrose). Recently, researchers reported successful use of TNK in peripheral thromboembolic disease (11) and in submassive pulmonary embolus. (12) However, there are no reports of TNK's use in the setting of cardiac arrest until now.

Case Report

A 79-year-old man in previously good health except for hypertension was admitted to the hospital for an elective right total knee replacement. On postoperative day 1, he was placed on 5 mg nightly of warfarin along with intermittent pneumatic compression device for deep venous thrombosis prophylaxis therapy. Early on postoperative day 3, he suddenly developed cardiorespiratory arrest with an initial rhythm of asystole. Chest compressions and basic life support were initiated within 60 seconds of collapse (t = 1 min). Commencing at t = 5 minutes after collapse, sequential doses of epinephrine and atropine were administered. At t = 10 minutes, the asystole converted to refractory ventricular fibrillation. At t = 34 minutes, the patient still did not have ROSC despite endotracheal intubation, five attempts at defibrillation, and the use of epinephrine, lidocaine, and procainamide. The cardiac arrest team made a presumptive diagnosis of fulminant pulmonary embolism. Using the manufacturer's weight-based nomogram (Table 2), TNK 50 mg over 5 seconds was administered intravenously at t = 34 minutes. Within two minutes the patient demonstrated ROSC. His immediate blood pressure was 108/61 and his heart rate was 106 with a sinus mechanism. He was transferred to the intensive care unit and continued on mechanical ventilation. A follow-up electrocardiogram showed no myocardial ischemia. The Doppler ultrasound of his left extremity was normal, while a nuclear perfusion scan was read as low probability for pulmonary embolism. The patient remained comatose with a presumptive hypoxic encephalopathy. A computed tomographic scan of his head showed no signs of intracerebral hemorrhage. The following day, mechanical ventilation was withdrawn and the patient expired.

Discussion

Fulminant pulmonary embolism causing cardiac arrest may potentially be reversed by immediate use of thrombolytic therapy. In our case, TNK was temporally associated with ROSC during refractory cardiac arrest. Despite a maximal 50 mg dose, there was no apparent intracranial or operative-site hemorrhage. Unfortunately, the patient survived less than 24 hours, apparently dying of hypoxic encephalopathy due to the prolonged cardiac arrest state. The diagnosis of fulminant pulmonary embolism was made clinically because of the refractory cardiac arrest, and his high postoperative risk for thromboembolic disease. The diagnostic confirmation of pulmonary embolism was admittedly equivocal here, but successful clot lysis may have altered the subsequent radiologic findings.

TNK, a genetically engineered variant of tPA, has more fibrin specificity, a longer plasma half-life, and equivalent lytic potency. (13,14) In clinical trials of acute myocardial infarction, TNK demonstrated equal efficacy and superior safety when compared with tPA. (9,10) Significant medication errors in an emergency situation may be less likely with TNK than with tPA because of its simpler dosing regimen. (14,15) It can be stored at room ambient temperature as a lyophilized powder until reconstituted, and bolus injection takes only 5 seconds.

To establish long-term survival benefit for thrombolytics in cardiac arrest, researchers and clinicians must develop strict selection criteria to identify those refractory cardiac arrest victims who are most likely to benefit from thrombolytic therapy. Rapid bedside evaluation with echocardiography, (16-19) capnometry, (20,21) and clinical parameters (2,16) may eventually prove helpful. Certainly thrombolytic therapy would be contraindicated in patients with refractory cardiac arrest due to toxic-metabolic causes, hypovolemia, tension pneumothorax, or cardiac tamponade. The other key link in this chain of survival is to develop a system for rapid administration of the thrombolytic after fulminant pulmonary embolism is diagnosed.

Conclusion

Because of its clinical equivalency and its logistical advantages, TNK should be evaluated as an attractive alternative over other thrombolytics in future trials of cardiac arrest.

We didn't lose the game; we just ran out of time.
--Vince Lombardi

Table 1. Ideal properties of thrombolytic agents for treating refractory
cardiac arrest (a)

Property                  TNK                    tPA

FDA approved for massive  No                     Yes (but only for 100
  pulmonary embolus?                             mg X 2 hour dosing
                                                 regimen)
Rapid bolus route?        Yes. Over 5 seconds.   Yes. Several regimens
                                                 described, including
                                                 over 15 minutes. (7)
Can be stored at room     Yes                    Yes
  temperature?
Low incidence of major    4.7% (10) (P < 0.05)   5.9% (10) (P < 0.05)
  hemorrhage requiring
  transfusion
Low incidence of          4.7% (10)              5.9% (10)
  intracranial
  hemorrhage
Logistical ease of        Possibly easier than   Possibly more
  administration          tPA. 1.3% dosing       difficult. 3.4% dosing
                          error rate. (15)       error rate. (15)

(a) TNK, tenecteplase; tPA, tissue plasminogen activator; FDA, US Food
and Drug Administration.

Table 2. Weight-based tenecteplase dosing (a)

Patient                                        Reconstituted
weight (kg)                          TNK (mg)   TNK (mL)

<60                                    30            6
[greater than or equal to]60 to <70    35            7
[greater than or equal to]70 to <80    40            8
[greater than or equal to]80 to <90    45            9
[greater than or equal to]90           50           10

(a) TNK, tenecteplase.

Accepted June 14, 2004.

References

1. Cobb LA, Fahrenbruch CE, Olsufka M, et al. Changing incidence of out-of-hospital ventricular fibrillation, 1980-2000. JAMA 2002;288:3008-3013.

2. Kurkciyan I, Meron G, Behringer W, et al. Accuracy and impact of presumed cause in patients with cardiac arrest. Circulation 1998;98:766-771.

3. Silfvast T. Cause of death in unsuccessful prehospital resuscitation. J Int Med 1991;229:331-335.

4. Lederer W, Lichtenberger C, Pechlaner C, et al. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation 2001;50:71-76.

5. Bailen MR, Cuadra JA, Aguayo De Hoyos E. Thrombolysis during cardiopulmonary resuscitation in fulminant pulmonary embolism: a review. Crit Care Med 2001;29:2211-2219.

6. Newman DH, Greenwald I, Callaway CW. Cardiac arrest and the role of thrombolytic agents. Ann of Emerg Med 2000;35:472-480.

7. Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Eng J Med 2002;346:1522-1528.

8. Bottiger BW, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet 2001;357:1583-1585.

9. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-613.

10. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen Investigators. Lancet 1999;354:716-722.

11. Razavi MK, Wong H, Kee ST, et al. Initial clinical results of tenecteplase (TNK) in catheter-directed thrombolytic therapy. J Endovascular Ther 2002;9:593-598.

12. Sze DY, Carey MB, Razavi MK. Treatment of massive pulmonary embolus with catheter-directed tenecteplase. J Vascular Intervent Radiol 2001;12:1456-1457.

13. Benedict CR, Refino CJ, Keyt BA, et al. New variant of human tissue plasminogen activator (TPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation 1995;92:3032-3040.

14. Llevadot J, Giugliano RP, Antman EM. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA 2001;286:442-449.

15. Murphy SA, Gibson CM, Van de Werf F, et al. Comparison of errors in estimating weight and in dosing of single-bolus tenecteplase with tissue plasminogen activator (TIMI 10B and ASSENT 1). Am J Cardiol 2002;90:51-54.

16. Kurkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome, Arch Int Med 2000;160:1529-1535.

17. MacCarthy P, Worrall A, McCarthy G, et al. The use of transthoracic echocardiography to guide thrombolytic therapy during cardiac arrest due to massive pulmonary embolism. Emerg Med J 2002;19:178-179.

18. Bocka JJ, Overton DT, Hauser A. Electromechanical dissociation in human beings: an echocardiographic evaluation. Ann Emerg Med 1988;17:450-452.

19. Varriale P, Maldonado JM. Echocardiographic observations during in hospital cardiopulmonary resuscitation. Crit Care Med 1997;25:1717-1720.

20. Wiegand UK, Kurowski V, Giannitsis E, et al. Effectiveness of end-tidal carbon dioxide tension for monitoring thrombolytic therapy in acute pulmonary embolism. Crit Care Med 2000;28:3588-3592.

21. Levine RL, Wayne MA, Miller CC. End-tidal carbon dioxide and outcome of out-of-hospital cardiac arrest. N Engl J Med 1997;337:301-306.

RELATED ARTICLE: Key Points

* Thrombolytics may occasionally reverse cardiac arrest, especially those cases due to fulminant pulmonary embolism.

* Studies with existing agents have showed equivocal outcomes.

* Tenecteplase has some logistical and pharmacologic advantages over other thrombolytics, and should be considered if standard advanced cardiac life support measures fail.

LTC Bruce D. Adams, MD, MC, USA, MAJ James Y. Kim, MD, MC, USA, and Walter O. Jackson, MD

From the Departments of Emergency Medicine and Cardiology, Brooke Army Medical Center, Fort Sam Houston, TX, and the Department of Emergency Medicine, Medical College of Georgia, Augusta, GA.

Reprint requests to LTC Bruce D. Adams, MD, MC, US Army, Department of Emergency Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas 78234. Email: [e-mail]