Thrombolysis in Cardiac Arrest
Author: Philip Jarrett, MD, MBA (Emergency Medicine, University of Texas Southwestern Medical Center) // Reviewed by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)
We pride ourselves as expert resuscitationists. We train to optimize every facet of cardiac arrest management from chest compression fraction and medication selection to team dynamics and debriefs. Hospital resources are expended at a hurried pace as plastic packaging collects on the floors and empty glass vials aggregate. We contemplate reversible causes as the clock ticks down to oblivion. Bedside ultrasound shows a dilated right ventricle. Thrombolytics are drawn up and pushed. Maybe it’s a pulmonary embolism (PE)…
PE is the cause of approximately 3-5% of cardiac arrests.1-3 This diagnosis plagues our minds as one of the most considered differential diagnoses in emergency medicine. With the broad availability of oral Xa inhibitors (and XIa agents on the way4), treatment is decreasingly invasive for most patients. More nuanced discussions remain on the topic of risk stratification and disposition, but even among cases of impending cardiovascular collapse, thrombolysis has become a mainstay of treatment with mounting evidence to support its benefit.5,6 If all else fails, many institutions are finding success with thrombectomy, catheter-directed thrombolysis, and even ECMO!7 Our toolbox is rounding out for PE where historical practice drew from far fewer available interventions, but, what if the patient lacks a pulse? This article will review the most noteworthy evidence in the emergency medicine literature to decipher whether, and when, thrombolysis may be appropriate to treat cardiac arrest if PE is a suspected cause.
The PEAPETT Study (2016)
This case series evaluated whether a population of patients with confirmed PE in pulseless electrical activity (PEA) would benefit from half-dose alteplase (tPA).8 Patients were retrospectively enrolled after a diagnosis of PE was made. These patients were followed prospectively to measure the effect of thrombolysis when cardiac arrest occurred. Of the 23 patients who suffered cardiac arrest, 17 occurred in the emergency department while two were in the intensive care unit, one was in a floor bed and three were in the radiology department. After administration of half-dose tPA, return of spontaneous circulation (ROSC) was achieved in 22 of the 23 studied patients. Furthermore, 87% of patients survived to 22 +/- 3 months of follow-up.
All-comers with in-hospital cardiac arrest (IHCA) in the United States (US) prior to the initial COVID surge suffered a mortality of 24.2%.9 Compared against this broader population, the PEAPETT outcomes boast a number-needed-to-treat (NNT) of 1.6 for survival to 22 months (Figure 1). It is not an entirely fair assessment to derive a NNT across unrelated studies, but could tPA be the wonder drug for patients who suffer a PEA arrest?
Not so fast! In this cohort without controls, the time to administration of thrombolytics was 6.5 +/- 2.1 minutes. Evidenced by at least one study and the anecdotal experience of my own institutions, most cardiac arrests begin in the pre-hospital setting.10And when the US national average arrival time for emergency medical services is 7.0 minutes in urban settings and 14.5 minutes in rural settings, the chance of receiving thrombolysis as quickly as patients in this case series falls flat.11 Thrombolysis may work under ideal conditions among admitted patients with a known diagnosis, but ideal conditions are few and far between in the realm of emergency medicine.
The TROICA Trial (2008)
A double-blinded, multicenter, randomized controlled trial published in the New England Journal of Medicine evaluated a broader population of patients who suffered witnessed out-of-hospital cardiac arrest (OHCA).2 Böttiger, et al successfully enrolled 1,050 patients and assigned 1:1 treatment of either placebo or Tenecteplase (tNK). Pre-hospital intensive care paramedics administered treatment on-scene prior to hospital transport. The trial was terminated early due to futility.
For the primary endpoint, the tNK cohort achieved a 30-day survival of 14.7% compared to 17.0% in the placebo group (Figure 2). For the secondary endpoint of ROSC at any point, tNK offered no benefit over placebo (55.0% vs. 54.6%, respectively; P = 0.96). Clearly, there is no benefit to administration of thrombolytics among all-comers, and with the astronomical price of thrombolytics in the U.S., the cost-benefit analysis to stock this medication in every ambulance for pre-hospital care may never add up.12 So, was the PEAPETT trial a fluke?
The Javaudin Study (2019)
A retrospective, observational, multi-center study published in CHEST asked whether a subgroup of OHCA patients who had subsequent confirmation of PE stood to benefit from pre-hospital administration of thrombolytics.13 These patients coded in the pre-hospital setting, received thrombolysis, and then had a confirmatory study or autopsy showing PE.
Among 328 patients with a final diagnosis of PE, 246 were evaluated in the study. The 82 excluded patients were removed either because ROSC was achieved prior to arrival of the mobile intensive care unit (MICU) that coordinated study enrollment and drug administration, or because the ROSC status was initially unknown by the MICU upon arrival. Of the 246 included patients, 58 received thrombolysis.
As shown in Figure 3, 30-day survival in the thrombolysis group was significantly higher than the placebo group (16% vs. 6%; P = 0.05). However, good neurologic outcome among survivors in each group did not differ (Adjusted Relative Risk, 1.97; 95% CI, 0.70 – 5.56). This study appropriately tempers the conclusions of the PEAPETT trial for emergency physicians, wherein the NNT for 30-day survival among OHCA patients with confirmed PE settles at 10. But, we don’t practice emergency medicine with the retrospectoscope in hand. Nearly always, the patient in front of us is undifferentiated. How can we decipher which coding patients have a PE?
Predictors of PE in Cardiac Arrest (2016)
A publication in Circulation evaluated the well-described Sudden Death Expertise Center registry from Paris to shed light on patient factors that may predict PE-related cardiac arrest.3 Among the 2,926 patients who were admitted alive to a hospital, 82 had a confirmed diagnosis of PE. Factors predictive of PE included patients with initial non-shockable rhythms, female gender, and those with prior thromboembolism (Figure 4).
The combination of initial non-shockable rhythm and prior thromboembolism yielded a positive predictive value of 31% (95% CI, 19% – 42%) and a negative predictive value of 98% (95% CI, 97% – 98%). Now, there’s a population worthy of trialing thrombolysis! Granted, this study would benefit from external validation with much larger sample sizes. But no one ever said cardiac arrest research is easy.
Interestingly, exclusion of patients with right ventricular failure on echocardiogram found consistent results. This is troublesome. Bedside ultrasound has become the emergency physician’s third hand, manifesting within the 2020 Advanced Cardiac Life Support guidelines as a Class 2b Recommendation for standard patient evaluation during cardiac arrest.6,14 Although it may be used to evaluate for cardiac tamponade, tension pneumothorax, and right heart strain, more recent evidence has shown that it probably should not be used to aid in the decision to terminate resuscitation.15 So, what role does an evaluation of right heart strain play in the prediction of PE-related cardiac arrest?
Right Heart Strain in Cardiac Arrest
A prospective observational study published in Resuscitation in 2019 evaluated 33 OHCA patients presenting either with ongoing cardiopulmonary resuscitation (CPR) or ROSC.16 A 4-view transesophageal echocardiogram was obtained in all patients. Of note, 12% of cases thought to be in asystole were found to have fine ventricular fibrillation, prompting defibrillation. More importantly for the PE discussion, right ventricular dilation (RVD) was observed in 57% of intra-arrest cases. Though ultrasound evidence of RVD may be a poor physician’s guide to PE among living patients in one systematic review and meta-analysis (sensitivity: 53%, 95% CI: 45-61%; specificity: 83%, 95% CI: 74-90%)17, RVD was a typical finding during cardiac arrest in this population.
A separate Resuscitation article published in 2021 also evaluated right ventricular strain (RVS) via electrocardiogram (ECG).18 This retrospective cross-sectional study reviewed continuous ECG tracings on admitted patients who subsequently suffered IHCA. RVS was defined by the authors as, “progressive RV depolarization delay in lead V1 with at least one supporting finding of RV ischemia or right axis deviation.” In this study, 47% of patients developed evidence of RVS immediately prior to loss of pulses. The positive predictive value and negative predictive value of RVS for the diagnosis of a respiratory cause of cardiac arrest was 81% (95% CI, 64-95%) and 58% (95% CI, 36-81%), respectively. Among patients who underwent evaluation of PE either by autopsy or computed tomography angiogram of the chest, only 6/23 (26.1%) were confirmed. The right ventricle may not be as predictive of PE during cardiac arrest as we would hope.
PE is a challenging diagnosis to make during ongoing CPR. There is understandable temptation to consider thrombolysis for patients in cardiac arrest to address all reversible causes. However, the limited evidence on this topic fails to demonstrate benefit among the undifferentiated cardiac arrest patient. Consider early administration of thrombolysis for patients with a combination of predictive factors that support an increased likelihood of PE-related cardiac arrest. On the other hand, resist the urge to use signs of right heart strain as a sole indicator of this pathology. Of note, this article defers the discussion on duration of CPR after administration of thrombolytics due to the wide range of recommendations from various resuscitation authorities. Recommendations span 30 – 90 minutes after drug administration based on limited evidence.6,19
Pearls and Pitfalls
- Thrombolysis for the patient with undifferentiated cardiac arrest is unlikely to provide mortality benefit and is associated with tremendous financial cost.2,12
- Among patients with confirmed PE who code, thrombolysis should be considered and should be given as early as possible.8,13 The NNT may be as low at 10 in this rare cohort.
- Factors with predictive value for PE-related cardiac arrest that, in combination, should support thrombolysis include (in order of decreasing odds ratio): initial non-shockable rhythm, prior thromboembolism, absence of cardiac history, and female gender.3
- Right heart strain, in isolation, should not be used to select for thrombolysis candidates, given its high incidence among all-comers in cardiac arrest.16,18
- Henriksson CE, Frithiofsson J, Bruchfeld S, Bendz E, Bruzelius M, Djärv T. In-hospital cardiac arrest due to pulmonary embolism – Treatment and outcomes in a Swedish cohort study. Resusc Plus. 2021 Nov 1;8:100178. doi: 10.1016/j.resplu.2021.100178. PMID: 34766067; PMCID: PMC8571515.
- Böttiger BW, Arntz H-R, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25): 2651-2662.
- Bougouin W, Marijon E, Planquette B, Karam N, Dumas F, Celermajer DS, Jost D, Lamhaut L, Beganton F, Cariou A, Meyer G, Jouven X; Sudden Death Expertise Center. Factors Associated With Pulmonary Embolism-Related Sudden Cardiac Arrest. Circulation. 2016 Dec 20;134(25):2125-2127. doi: 10.1161/CIRCULATIONAHA.116.024746. PMID: 27994026.
- Quan ML, Pinto DJP, Smallheer JM, Ewing WR, Rossi KA, Luettgen JM, Seiffert DA, Wexler RR. Factor XIa Inhibitors as New Anticoagulants. J Med Chem. 2018 Sep 13;61(17):7425-7447. doi: 10.1021/acs.jmedchem.8b00173. Epub 2018 May 18. PMID: 29775297.
- Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, Nolan JP, Paal P, Perkins GD, Thies KC, Yeung J, Zideman DA, Soar J; ERC Special Circumstances Writing Group Collaborators. European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances. Resuscitation. 2021 Apr;161:152-219. doi: 10.1016/j.resuscitation.2021.02.011. Epub 2021 Mar 24. Erratum in: Resuscitation. 2021 Oct;167:91-92. PMID: 33773826.
- Panchal AR, Bartos JA, Cabañas JG, Donnino MW, Drennan IR, Hirsch KG, Kudenchuk PJ, Kurz MC, Lavonas EJ, Morley PT, O’Neil BJ, Peberdy MA, Rittenberger JC, Rodriguez AJ, Sawyer KN, Berg KM; Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. Epub 2020 Oct 21. PMID: 33081529.
- Yusuff HO, Zochios V, Vuylsteke A. Extracorporeal membrane oxygenation in acute massive pulmonary embolism: a systematic review. Perfusion. 2015 Nov;30(8):611-6. doi: 10.1177/0267659115583377. Epub 2015 Apr 24. PMID: 25910837.
- Sharifi M, Berger J, Beeston P, Bay C, Vajo Z, Javadpoor S; “PEAPETT” investigators. 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. Epub 2016 Jun 30. PMID: 27422214.
- Chan PS, Spertus JA, Kennedy K, Nallamothu BK, Starks MA, Girotra S. In-Hospital Cardiac Arrest Survival in the United States During and After the Initial Novel Coronavirus Disease 2019 Pandemic Surge. Circ Cardiovasc Qual Outcomes. 2022 Feb;15(2):e008420. doi: 10.1161/CIRCOUTCOMES.121.008420. Epub 2022 Jan 31. PMID: 35098727; PMCID: PMC8852282.
- Høybye M, Stankovic N, Holmberg M, Christensen HC, Granfeldt A, Andersen LW. In-Hospital vs. Out-of-Hospital Cardiac Arrest: Patient Characteristics and Survival. Resuscitation. 2021 Jan;158:157-165. doi: 10.1016/j.resuscitation.2020.11.016. Epub 2020 Nov 19. PMID: 33221361.
- Mell HK, Mumma SN, Hiestand B, Carr BG, Holland T, Stopyra J. Emergency Medical Services Response Times in Rural, Suburban, and Urban Areas. JAMA Surg.2017;152(10):983–984. doi:10.1001/jamasurg.2017.2230
- Julie Washington cleveland.com. ‘do something about this:’ one drug treatment cost $45,500; why prescription drug prices are so high and vary so much. Cleveland. https://www.cleveland.com/business/2021/11/one-drug-treatment-cost-45500-heres-why-prescription-prices-are-so-high-and-vary-so-much.html. Published December 1, 2021. Accessed November 17, 2022.
- Javaudin F, Lascarrou JB, Le Bastard Q, Bourry Q, Latour C, De Carvalho H, Le Conte P, Escutnaire J, Hubert H, Montassier E, Leclère B; Research Group of the French National Out-of-Hospital Cardiac Arrest Registry (GR-RéAC). Thrombolysis During Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Pulmonary Embolism Increases 30-Day Survival: Findings From the French National Cardiac Arrest Registry. Chest. 2019 Dec;156(6):1167-1175. doi: 10.1016/j.chest.2019.07.015. Epub 2019 Aug 2. PMID: 31381884.
- Paul JA, Panzer OPF. Point-of-care Ultrasound in Cardiac Arrest. Anesthesiology. 2021 Sep 1;135(3):508-519. doi: 10.1097/ALN.0000000000003811. PMID: 33979442.
- Reynolds JC, Del Rios M. Point-of-care cardiac ultrasound during cardiac arrest: a reliable tool for termination of resuscitation? Curr Opin Crit Care. 2020 Dec;26(6):603-611. doi: 10.1097/MCC.0000000000000766. PMID: 33002970.
- Teran F, Dean AJ, Centeno C, Panebianco NL, Zeidan AJ, Chan W, Abella BS. Evaluation of out-of-hospital cardiac arrest using transesophageal echocardiography in the emergency department. Resuscitation. 2019 Apr;137:140-147. doi: 10.1016/j.resuscitation.2019.02.013. Epub 2019 Feb 16. PMID: 30779977.
- Fields JM, Davis J, Girson L, Au A, Potts J, Morgan CJ, Vetter I, Riesenberg LA. Transthoracic Echocardiography for Diagnosing Pulmonary Embolism: A Systematic Review and Meta-Analysis. J Am Soc Echocardiogr. 2017 Jul;30(7):714-723.e4. doi: 10.1016/j.echo.2017.03.004. Epub 2017 May 9. PMID: 28495379.
- Do D.H., Yang J.J., Kuo A. Electrocardiographic right ventricular strain precedes hypoxic pulseless electrical activity cardiac arrests: looking beyond pulmonary embolism. 2020;151:127–134.
- Soar J, Böttiger BW, Carli P, Couper K, Deakin CD, Djärv T, Lott C, Olasveengen T, Paal P, Pellis T, Perkins GD, Sandroni C, Nolan JP. European Resuscitation Council Guidelines 2021: Adult advanced life support. Resuscitation. 2021 Apr;161:115-151. doi: 10.1016/j.resuscitation.2021.02.010. Epub 2021 Mar 24. Erratum in: Resuscitation. 2021 Oct;167:105-106. PMID: 33773825.
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