Correspondence
Tissue Plasminogen Activator in Cardiac Arrest with Pulseless Electrical Activity
N Engl J Med 2002; 347:1281-1282October 17, 2002
- Article
To the Editor:
In contrast to previous trials,1,2 the study reported by Abu-Laban et al. (May 16 issue)3 showed no beneficial effects of fibrinolysis in patients with cardiac arrest and pulseless electrical activity. However, Abu-Laban et al. studied a subgroup with an exceptionally poor prognosis.4 We are not aware of other studies in which there were no survivors in the placebo group. Even therapeutic strategies with proven efficacy in patients with cardiac arrest, such as hypothermia,5 would have failed in this study population. To test validly for efficacy, it is important to study populations that might also survive without specific treatment. Moreover, treatment with tissue plasminogen activator (t-PA) was initiated a mean of 36 minutes after the patient's collapse, by which time ineffective resuscitation procedures have mostly been terminated. Nevertheless, the group size was calculated on the assumption that treatment would change the rate of survival to hospital discharge from 1.0 percent (in the placebo group) to 10.3 percent (in the t-PA group) — an increase of 930 percent. Such prerequisites might a priori preclude the demonstration of any positive effect of an intervention.
In contrast to previous studies,1 the administration of heparin was not mandatory. Nevertheless, 5 of 13 patients (38 percent) who were admitted received heparin, which may suggest an additional beneficial effect. Therefore, the number of patients per group who received this medication should be clarified.
For conclusive investigation of the effects of t-PA in cardiac arrest, t-PA must be given early to patients with a better prognosis, such as those with a witnessed arrest, ventricular fibrillation, or both. Such a study is currently under way in Europe, and when the results are available, the controversy over fibrinolysis in cardiac arrest can be resolved.
5 ReferencesBernd W. Böttiger, M.D.
Stephan A. Padosch, M.D.
University of Heidelberg, 69120 Heidelberg, Germany
bernd_boettiger@med.uni-heidelberg. de Volker Wenzel, M.D.
University of Innsbruck, 6020 Innsbruck, Austria1
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
CrossRef | Web of Science | Medline2
Lederer W ,Lichtenberger C ,Pechlaner C ,Kroesen G ,Baubin M . Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation 2001;50:71-76
CrossRef | Web of Science | Medline3
Abu-Laban RB ,Christenson JM ,Innes GD , et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med 2002;346:1522-1528
Full Text | Web of Science | Medline4
Engdahl J ,Bang A ,Lindqvist J ,Herlitz J . Factors affecting short- and long-term prognosis among 1069 patients with out-of-hospital cardiac arrest and pulseless electrical activity. Resuscitation 2001;51:17-25
CrossRef | Web of Science | Medline5
The Hypothermia after Cardiac Arrest Study Group
Full Text | Web of Science | Medline
To the Editor:
Fibrinolytic, antiplatelet, and antithrombotic agents are promising for the treatment of cardiac arrest. Cardiopulmonary resuscitation (CPR) can alter the pharmacokinetics of these agents, making higher dosages or bolus administration necessary. Laboratory studies must therefore precede clinical trials. We have previously noted that the grave nature of cardiac arrest may explain the tendency to rush into clinical trials, but it may not justify the potential harm from false negative findings.1
Concern about the administration of a potentially harmful agent under “implied consent” may not be mitigated by using it late, when it may be ineffective. In this study, fibrinolysis may not have been achieved before irreversible injury occurred.
Perfusion pressure during CPR is the difference between arterial and venous pressures.2 The administration of 500 ml of intravenous saline is not standard practice and may decrease perfusion. Bicarbonate is additional volume, and lidocaine's sodium-channel blockade may cause asystole3 — neither agent is part of standard therapy.
Because fewer patients who underwent autopsy had pulmonary embolism or acute myocardial infarction than in other series,4 less than one quarter may have been susceptible to a benefit. The inclusion of patients with initial asystole also reduced the proportion with a potential response. This study population may not have been optimal, since other medical systems have had better results with pulseless electrical activity.5 We refer to this as a “graveyard effect”; a better term might be “rancid sample,” as proposed by the late epidemiologist Dr. Alvan Feinstein. This study does not “exclude” an increase in survival, because when the control outcome is zero, the efficacy remains unknown.
5 ReferencesNorman A. Paradis, M.D.
University of Colorado Health Sciences Center, Denver, CO 80010Andrew Knaut, M.D., Ph.D.
Denver Health Medical Center, Denver, CO 80204Henry Halperin, M.D.
Johns Hopkins Hospital, Baltimore, MD 21287-65681
Paradis NA . Cardiac arrest research in humans -- insights into failure. Resuscitation 1996;31:93-100
CrossRef | Web of Science | Medline2
Paradis NA ,Martin GB ,Rivers EP , et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113
CrossRef | Web of Science | Medline3
Cairns CB ,Paradis NA . Empiric lidocaine: deja vu (all over again?). Ann Emerg Med 2000;36:626-627
CrossRef | Web of Science | Medline4
Comess KA ,DeRook FA ,Russell ML ,Tognazzi-Evans TA ,Beach KW . The incidence of pulmonary embolism in unexplained sudden cardiac arrest with pulseless electrical activity. Am J Med 2000;109:351-356
CrossRef | Web of Science | Medline5
Zoch TW ,Desbiens NA ,DeStefano F ,Stueland DT ,Layde PM . Short- and long-term survival after cardiopulmonary resuscitation. Arch Intern Med 2000;160:1969-1973
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We disagree with the suggestion that our study was predestined to have negative results. Böttiger et al. state that t-PA must be evaluated in patients with a witnessed arrest, initial ventricular fibrillation, or both. Sixty-six percent of our study population met this requirement. Paradis et al. question research on subgroups with poor outcomes; however, it has not been established that a high base-line survival rate is required to assess the management of pulseless electrical activity validly. We specifically studied this rhythm because of its association with pulmonary embolism1 and the documented potential for forward blood flow and good outcomes despite prolonged pulselessness. Most reports on fibrinolysis involve cases in which patients have pulseless electrical activity and are expected to die, yet a review of 67 such cases showed a 75 percent survival rate and a mean duration of arrest of 51 minutes.2 Our sample-size requirement was based on these reports and a more modest survival rate of 30 percent for the targeted subgroup.
We anticipated that 1 percent of eligible patients would survive; thus, the outcome in our placebo group was not surprising. Of 467 ineligible patients with pulseless electrical activity, 4.7 percent survived. Most such survivors have an early response to the initial therapies that we thought would have been inappropriate to omit before the administration of t-PA. Intravenous saline is considered standard therapy for pulseless electrical activity by the British Columbia Ambulance Service. The influence of fluids on perfusion pressure, with the various causes of pulseless electrical activity, remains poorly understood. Neither bicarbonate nor lidocaine was mandated by our protocol, and the proportions of patients who received these agents reflect local practice.
We believe our time intervals represent the reality of out-of-hospital administration of a reconstituted fibrinolytic agent after a rapid trial of initial therapies. On the basis of numerous reports, these intervals would not negate the possibility of a response. Unfortunately, the studies with positive results are methodologically weak and provide no data on timing,3,4 precluding a comparison with our trial. In response to the question about heparin, of the five patients who were given heparin, three received t-PA.
We agree that laboratory studies are helpful but certainly do not believe we rushed into a clinical trial. Our study arose logically from a foundation of numerous reports involving humans, as did two recent articles calling for clinical trials of fibrinolytic agents in cardiac arrest.2,5 In our article, we candidly discuss the limitations of our study, many of which the correspondents repeat, and note that our results do not exclude the possibility of a role for fibrinolytic therapy. Although we stand by our conclusions, we look forward to the results of the European trial and other trials.
5 ReferencesRiyad B. Abu-Laban, M.D., M.H.Sc.
James M. Christenson, M.D.
Grant D. Innes, M.D.
University of British Columbia, Vancouver V6T 1Z3, Canada
abulaban@interchange.ubc. ca 1
Courtney DM ,Sasser HC ,Pincus CL ,Kline JA . Pulseless electrical activity with witnessed arrest as a predictor of sudden death from massive pulmonary embolism in outpatients. Resuscitation 2001;49:265-272
CrossRef | Web of Science | Medline2
Newman DH ,Greenwald I ,Callaway CW . Cardiac arrest and the role of thrombolytic agents. Ann Emerg Med 2000;35:472-480
Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
Lederer W ,Lichtenberger C ,Pechlaner C ,Kroesen G ,Baubin M . Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation 2001;50:71-76
CrossRef | Web of Science | Medline5
Kern KB . Thrombolytic therapy during cardiopulmonary resuscitation. Lancet 2001;357:1549-1550
CrossRef | Web of Science | Medline
- Citing Articles (13)
Citing Articles
1
Spyros D. Mentzelopoulos, Spyros G. Zakynthinos, Ilias Siempos, Sotiris Malachias, Hanno Ulmer, Volker Wenzel. (2011) Vasopressin for cardiac arrest: Meta-analysis of randomized controlled trials. Resuscitation
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J. Kreutziger, P.-P. Ellmauer, K.H. Lindner, V. Wenzel. (2010) Vasopressoren bei der kardiopulmonalen Reanimation. Notfall + Rettungsmedizin 13:4, 274-280
CrossRef3
Janett Kreutziger, Volker Wenzel. (2009) Overcoming frustration about neutral clinical studies in cardiopulmonary resuscitation. Resuscitation 80:7, 723-725
CrossRef4
Fabian Spöhr, Volker Wenzel, Bernd W Böttiger. (2008) Thrombolysis and other drugs during cardiopulmonary resuscitation. Current Opinion in Critical Care 14:3, 292-298
CrossRef5
William P. Bozeman, Douglas M. Kleiner, Kevin L. Ferguson. (2006) Empiric tenecteplase is associated with increased return of spontaneous circulation and short term survival in cardiac arrest patients unresponsive to standard interventions. Resuscitation 69:3, 399-406
CrossRef6
Fabian Sp??hr, Volker Wenzel, Bernd W. B??ttiger. (2006) Drug treatment and thrombolytics during cardiopulmonary resuscitation. Current Opinion in Anaesthesiology 19:2, 157-165
CrossRef7
F. Spohr, H. R. Arntz, E. Bluhmki, C. Bode, P. Carli, D. Chamberlain, T. Danays, J. Poth, C. Skamira, V. Wenzel, B. W. Bottiger. (2005) International multicentre trial protocol to assess the efficacy and safety of tenecteplase during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest: The Thrombolysis in Cardiac Arrest (TROICA) Study. European Journal of Clinical Investigation 35:5, 315-323
CrossRef8
Alfred P. Hallstrom, Norman A. Paradis. (2005) Pre-randomization and de-randomization in emergency medical research: new names and rigorous criteria for old methods. Resuscitation 65:1, 65-69
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Peter Vogel, Herman v.d. Putten, Erik Popp, Jakub J. Krumnikl, Peter Teschendorf, Roland Galmbacher, Malgorzata Kisielow, Christoph Wiessner, Albert Schmitz, Kevin J. Tomaselli, Bernd Schmitz, Eike Martin, Bernd W. Böttiger. (2003) Improved Resuscitation after Cardiac Arrest in Rats Expressing the Baculovirus Caspase Inhibitor Protein p35 in Central Neurons. Anesthesiology 99:1, 112-121
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Travis Anderson, Terry L. Vanden Hoek. (2003) Preconditioning and the oxidants of sudden death. Current Opinion in Critical Care 9:3, 194-198
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William P. Bozeman. (2003) Empiric thrombolysis in prehospital cardiac arrest: sodium bicarbonate use may obscure benefit. Resuscitation 57:2, 215-216
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B. W. Bottiger, F. Spohr. (2003) The risk of thrombolysis in association with cardiopulmonary resuscitation: no reason to withhold this causal and effective therapy. Journal of Internal Medicine 253:2, 99-101
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Fabian Sp??hr, Bernd W B??ttiger. (2003) Safety of Thrombolysis during Cardiopulmonary Resuscitation. Drug Safety 26:6, 367-379
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