A cardiac catheterization laboratory-based ECPR protocol at the University of Minnesota utilized a high volume/expertise group of interventional/critical care cardiologists to start and management ECMO upon arrival of the patient. Photo courtesy Demetris Yannopoulos.
The dawn of a new era
Although ventricular tachycardia/ventricular fibrillation (v tach/v fib) constitutes only 25-35% of all cardiac arrests, more than 80% of all cardiac arrest survivors with favorable neurological function present with v tach/v fib.1,2 (See Figure 1.) Despite that, only one third (approximately 30%) of patients presenting initially with v tach/v fib survive to hospital discharge with good neurological function.
Compared to the other presenting rhythms (asystole and pulseless electrical activity) v tach/v fib is associated with the highest survival and stands out as the most important positive predictive factor for neurological intact survival with odd ratios ranging from 15 to > 40.3 As such, v fib remains a very important target to improve overall survival since it represents patients that are viable.
Over the last 20 years, a significant body of evidence has emerged highlighting the importance of significant coronary artery disease in patients presenting with v tach/v fib and out-of-hospital cardiac arrest (OHCA).4-8 The accumulated evidence in regard to the presence of coronary artery disease has introduced significant scientific questions about the role of diagnostic and interventional procedures aiming to identify and reverse the potential cause of the arrest. Currently the American Heart Association recommends all patients resuscitated from first presenting shockable rhythms that have ST elevation on the post-resuscitation ECG gain access to the cardiac catheterization lab (CCL) per standard ST-elevation myocardial infarction guidelines-even if they're comatose.9,10
For patients that have no ST elevation, there's varied treatment practices, with early CCL access and ICU initial access followed by cardiology consultation as needed. The PEARL and the ACCESS trials are currently evaluating these two major approaches currently in the United States and results will be available the next few years.
The Emergence of ECMO
Recent developments in the use of extracorporeal membrane oxygenation (ECMO) and clinical advancements have introduced a significant additional means in the fight against refractory cardiac arrest.
Peripheral veno-arterial ECMO is the only kind of ECMO that's used during CPR. The combination of the two is called extracorporeal CPR (ECPR).11 ECPR is performed via percutaneous techniques with ultrasound guidance and or surgical cut down techniques at the femoral vessels under ongoing CPR.12,13 Venous cannulas (usually 25 F) are inserted all the way to the right atrium where they uptake all the returning venous blood into the ECMO circuit.
The venous blood falls into a chamber that comes into close contact with oxygen and air flowing through microporous tubes (oxygenator). In this chamber, blood gets oxygenated and CO2 is removed similarly to the function of the lung. The oxygenated blood is then returned with the use of a mechanical pump and under pressure into the descending abdominal aorta or the common iliac artery and, in a retrograde fashion, perfuses the whole body. Devices have been miniaturized significantly over the last five years and are now mobile-about the size of a small desktop computer monitor.
ECMO initiation now can be undertaken in the CCL, EDs and even the streets of a city. The advancement of automated CPR devices, such as the LUCAS and Autopulse, has revolutionized the way that refractory cardiac arrest patients can be treated with either longer periods of CPR or with early mobilization strategies where the patient now can be transferred to an advanced resuscitation center for ECPR initiation and coronary angiography and possible percutaneous coronary intervention (PCI).
Since there are no randomized trials in humans to assess the therapeutic options for ischemic refractory v fib cardiac arrest, we will attempt to evaluate below the benefit of coronary revascularization to survival and ECMO-facilitated revascularization on short-term survival from randomized animal studies and multiple human cohorts.
One study used an established pig model in which occlusion of the left anterior descending (LAD) coronary artery was induced via balloon inflation.14 After 5 minutes, v fib was induced and left untreated for 8 minutes. CPR was performed for 3 minutes, and advanced cardiac life support (ACLS) was performed until return of spontaneous circulation (ROSC) was achieved or the pig had received 15 minutes of CPR.
Of 27 pigs, 21 had ROSC within 15 minutes. Six pigs didn't have ROSC within 15 minutes and were classified as having refractory v fib. If ROSC wasn't achieved in these six pigs within 45 minutes of continued ACLS, reperfusion was attempted via LAD balloon deflation and removal with continued CPR until ROSC or another 10 minutes of resuscitation. ROSC was achieved in four of the six animals with refractory v fib, but only after ECMO reperfusion
This study is relevant because it shows that in refractory ischemic v fib arrest that doesn't respond to standard ACLS, coronary revascularization/reperfusion appears to be necessary for ROSC. Because patients with refractory v fib have a very high rate of acute and chronic coronary artery disease, PCI may be their only option for successful resuscitation.
Another study reported the results of ischemic refractory v fib in 33 intubated and anesthetized female pigs (44±3 kg).15 V fib was induced by endovascular balloon occlusion of the ostial LAD.
After five minutes of untreated v fib and 10 minutes of CPR, pigs were randomized to LAD reperfusion at minute 45 with ongoing CPR without ECMO (16 pigs) vs. venoarterial ECMO cannulation at minute 45 of CPR (17 pigs) and subsequent LAD reperfusion. Resuscitation continued until ROSC was achieved or 60 minutes of CPR had elapsed. Animals without ROSC at 60 minutes were declared dead. Resuscitated animals were maintained for four hours. The primary endpoint was 4-hour survival.
Results of this study showed that4-hour survival was significantly improved in pigs with ECMO (82%) compared to those without ECMO (31%, p = 0.003). After four hours, nine pigs with ECMO were suitable for decannulation.
The study concluded that ECMO-facilitated coronary reperfusion significantly improved 4-hour survival compared with reperfusion facilitated by CPR alone. ECMO support enabled cardiac recovery and hemodynamic stability within four hours. These results support the idea that, although coronary reperfusion is a necessary condition for achieving ROSC, after prolonged (45 minutes) CPR the metabolic ischemic substrate requires circulatory support to improve outcomes.
Human Clinical Studies
In 2016, according to the Extracorporeal Life Support Organization (ELSO), survival to discharge following ECPR for cardiac arrest that's refractory to conventional CPR was 29% in their registry database of 2,885 adults.16 Published studies have reported widely varying results. Most of the experience is from cohorts outside of the U.S., mainly in Asia. 17-22
Several studies of patients unresponsive to CPR who received ECMO (and PCI when indicated) found worse outcomes with OHCA vs. in-hospital cardiac arrest (IHCA). One study analyzed data for 86 patients with OHCA or in-hospital cardiac arrest (IHCA) unresponsive to CPR who received ECMO (and PCI when indicated). Survival to day 30 was 29% overall, 17% (7/42) for OHCA vs. 41% (18/44) for IHCA, and 37% (17/46) for patients presenting with v tach/v fib vs. 20% (8/40) for patients with non-shockable rhythms.17
Compared with patients who didn't survive to day 30, survivors had a significantly shorter time interval from collapse to the initiation of ECMO (54 minutes [34-74 minutes] vs. 40 minutes [25-51 minutes], p = 0.002) and a higher rate of intra-arrest PCI (70% vs. 88%; p = 0.04).
No significant differences were observed between OHCA and IHCA in rate of survival to discharge (38.7% vs. 31.2%, p > 0.05) or functionally favorable outcome (25.8% vs. 25.1%, p > 0.05).
Duration of ischemia (collapse to ECPR) was a key issue for survival. The authors attributed the high survival rate in patients with OHCA compared to previous studies17,18,23,24 to a well-organized and rapid-response EMT system, efficiency in handling patient transportation and resuscitation, and an equipped cart in the ED rather than in the ICU, shortening the duration of ischemia.
In Australia, 26 patients with refractory prolonged cardiac arrest were treated with the CHEER protocol (mechanical CPR, hypothermia, ECMO and early reperfusion) during a period of 32 months. Of 15 patients with IHCA, all had ROSC with ECMO, and 9 (60%) survived. In 11 patients with OHCA (all with v fib), ROSC was achieved in two patients before ECMO was initiated and in eight of nine patients placed on ECMO. A total of five OHCA patients (45%) survived, including three of nine patients who were placed on ECMO.25
An Italian study reported on ECMO support in patients with refractory cardiac arrest (IHCA, n = 24; OHCA, n = 18). Survival to discharge from intensive care was 46% (11/24) for IHCA and 5% (1/18) for OHCA (p < 0.05). At six months, survival rates with good neurological outcome were 38% (9/24) for IHCA and 5% (1/18) for OHCA.23
A German study analyzed a total of 85 consecutive adult patients treated with ECLS. Thirty-day survival was 42% (25/59) in patients with IHCA and 15% (4/26) in patients with OHCA (p < 0.02). Duration of CPR was independent risk factor for mortality.24
In the U.S., one study reported 26 cases where patients received ECMO (and reperfusion when indicated) over a seven-year period, of whom 11 (42%) presented with v fib/v tach. Of 15 patients with OHCA, one patient (6.6%) who presented with v fib/v tach survived to discharge and made a full neurologic recovery. Survival to discharge was 27.3% (3/11) for IHCA.26
Inconsistent results were found in some studies comparing ECPR vs. conventional CPR in OHCA. A study from South Korea, found similar rates of survival to hospital discharge in OHCA patients with prolonged conventional cardiopulmonary resuscitation (CCPR) compared with patients who received ECPR (19.4% [86/444] vs. 16.4 [9/55]). However, propensity score matching of patients with ≥ 21 minutes of CPR duration showed neurological outcome at 3 months to be more favorable with ECPR than with CCPR (14.5 vs. 8.1%).22
A Japanese study analyzed data from 162 adult patients with witnessed OHCA of cardiac origin who had undergone cardiopulmonary resuscitation for longer than 20 minutes. Survival to discharge was 32.1% (17/53) with ECPR and 6.4% (7/109) with conventional CPR. Matched propensity analysis showed significantly higher neurologically intact survival at three months with ECPR vs. conventional CPR (29.2% vs. 8.3%; p = 0.018).18
The SAVE-J trial, a prospective observational study of OHCA patients with v fib/v tach performed in Japan over 3 years, compared patients admitted to 26 hospitals providing ECPR vs. those admitted to 20 hospitals that didn't provide ECPR. In per protocol analysis, overall one-month survival was 29% (68/234) with ECPR vs. 6% (9/159) in the non-ECPR group. CPC scores of 1 or 2 were achieved at one month in 13.7% (32/234) of patients who received ECPR vs. 1.9% (3/159) of those without ECPR (p < 0.0001), and at 6 months in 12.4% (29/234) vs. 3.1% (5/159) (p = 0.002).20
An Austrian study found that survival to discharge in good neurological condition was 14% (1/11) with ECPR and 6% (13/232) with conventional CPR.27
Several studies compared patients with refractory v fib/v tach vs. those with non-shockable rhythms. German researchers found 30-day survival was 37.5% (3/8) in patients presenting with v fib/v tach, and 35% (6/17) in patients presenting with non-shockable rhythms. The door-to-ECLS implantation time was the only significant and independent predictor of 30-day mortality.28
A study from Denmark found that of 21 adult patients admitted with witnessed, refractory, normothermic OHCA treated with ECPR, seven (33%) survived to hospital discharge, all with a CPC score of 1 or 2. Survival to hospital discharge was 55.6% (5/9) in patients with v fib/v tach as the initial rhythm and 16.7% (2/12) in patients presenting with pulseless electric activity or asystole.29
In patients with refractory OHCA who received ECPR in Lyon, France, survival to discharge was 31.5% (6/19) for v fib/v tach and 0% (0/49) for non-shockable rhythms (p = 0.00).30
In patients who received ECMO for refractory OHCA in South Korea, 30-day survival was 40% (8/20) for patients with v fib/v tach, and 67% (2/3) for patients with non-shockable rhythms.
In a study in Paris, although overall survival in patients with refractory OHCA and ECPR was 13.5% (21/156), early field application of ECMO within 60 minutes from a 9-1-1 call, and careful selection of patients, improved survival from 8% to 29%. Absence of coronary angiography was the strongest predictor of mortality (OR 7.1), and only patients presenting with v fib/v tach were among the survivors.31
In 62 consecutive adult patients treated with the Minnesota Refractory V Fib/V Tach Protocol, 45% (28/62) of patients were discharged alive and 42% (26/62) were discharged with favorable neurological function (CPC 1 or 2).32
This recently published study showed a three-fold increase in survival compared to historical controls. (See Figure 2, p. 14.) The main effect of ECPR was a 2.5-fold higher ICU admission rate compared to historical controls. ECMO-based resuscitation provided the hemodynamic and respiratory support for 45% of those patients to survive to hospital discharge. Cardiac function recovered almost universally as it can be seen in the figure below based on survivors and non-
survivors. (See Figure 3, p. 14.) Over two years, the University of Minnesota has treated with its CCL based ECPR protocol 121 patients. Survival has remained unchanged to 45%.
The University of Utah has developed a similar program based on ED ECPR initiation in conjunction with an early transport systems-based protocol and have reported very encouraging 35% survival rates in the first 17 patients over the last two years.33
Words of Caution
Although ECLS provides a very promising new tool in the armamentarium to treat OHCA, full patient recovery requires a supporting system of care after the intervention that needs to be better understood and essentially redefined.
Odds of survival after cardiac arrest increase in hospitals with full cardiovascular interventional capabilities, even when patients don't have specific interventions.34,35
This observation suggests the culture of care is different between sites, and we speculate that experience improves care for patients with acute cardiovascular collapse.
Post-cardiac arrest intensive care has multiple organ facets.36 The most common cause of death after reversal of cardiac arrest remains withdrawal of life support because of presumed neurological devastation.34
Accurate neurological prognostication is still an area of research, and neurocritical care expertise can be essential to prevent premature withdrawal for patients with potential for recovery.37
Every other organ system is also affected by ischemia-reperfusion.38 Therefore, multidisciplinary critical care, including access to support services for all organ failures, may be necessary for any post-arrest patient.
The full post-intensive care management palette of rehabilitation and secondary prevention are essential to sustain the survival gains that are achieved early with aggressive ECPR-based programs.
Access to implantable defibrillators cognitive, functional and physical impairment management are all paramount in the system preparation for advanced ECPR based protocol initiations.
Need for a Randomized Trial
According to the 2015 American Heart Association guidelines, "there is insufficient evidence to recommend the routine use of ECPR for patients with cardiac arrest."39 In studies published since 2015, survival ranged from 8.8% to 43.5% for ECPR in patients with OHCA,21,27,29-32 and up to 55.6% in patients with v fib/v tach OHCA.29 (See Table 1.)
Although these results are encouraging, most reports were retrospective, and all studies were observational, with inherent selection bias that no statistical adjustment can eliminate completely.
No randomized clinical trials have been performed. Wide variation in results stems from heterogeneous study populations, varying bystander intervention, differences in prehospital EMS organizations, the lack of a standardized protocol for ECPR with ECMO in refractory cardiac arrest, differences in in-hospital care, and differences in outcome criteria have resulted in widely varying findings in published study results.
ECPR and ECMO use in the post-resuscitation management of patients of OHCA refractory cardiac arrest has yielded highly promising results by providing a therapeutic platform that, when applied early and within 60 minutes from the 9-1-1 call, can potentially double survival. Costs and infrastructure are major challenges. The need to assess the role of ECMO on survival with a randomized clinical trial has matured.
1. Adabag S, Hodgson L, Garcia S, et al. Outcomes of sudden cardiac arrest in a state-wide integrated resuscitation program: Results from the Minnesota Resuscitation Consortium. Resuscitation. 2017;110:95-100.
2. van Diepen S, Girotra S, Abella BS, et al. Multistate 5-year initiative to improve care for out-of-hospital cardiac arrest: Primary results from the HeartRescue Project. J Am Heart Assoc. 2017;6(9):e005716.
3. Debaty G, Labarere J, Frascone RJ, et al. Long-term prognostic value of gasping during out-of-hospital cardiac arrest. J Am Coll Cardiol. 2017;70(12):1467-1476.
4. Garcia S, Drexel T, Bekwelem W, et al. Early access to the cardiac catheterization laboratory for patients resuscitated from cardiac arrest due to a shockable rhythm: The Minnesota Resuscitation Consortium Twin Cities unified protocol. J Am Heart Assoc. 2016;5(1):e002670.
5. Camuglia AC, Randhawa VK, Lavi S, et al. Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: Review and meta-analysis. Resuscitation. 2014;85(11):1533-1540.
6. Garot P, Lefevre T, Eltchaninoff H, et al. Six-month outcome of emergency percutaneous coronary intervention in resuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation. 2007;115(11):1354-1362.
7. Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med. 1997;336(23):1629-1633.
8. Voicu S, Sideris G, Deye N, et al. Role of cardiac troponin in the diagnosis of acute myocardial infarction in comatose patients resuscitated from out-of-hospital cardiac arrest. Resuscitation. 2012;83(4):452-458.
9. Peberdy MA, Donnino MW, Callaway CW, et al. Impact of percutaneous coronary intervention performance reporting on cardiac resuscitation centers: a scientific statement from the American Heart Association. Circulation. 2013;128(7):762-773.
10. O'Connor RE, Brady W, Brooks SC, et al. Part 10: Acute coronary syndromes: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S787-S817.
11. Debaty G, Babaz V, Durand M, et al. Prognostic factors for extracorporeal cardiopulmonary resuscitation recipients following out-of-hospital refractory cardiac arrest. A systematic review and meta-analysis. Resuscitation. 2017;112:1-10.
12. Yannopoulos D, Bartos JA, Martin C, et al. Minnesota Resuscitation Consortium's advanced perfusion and reperfusion cardiac life support strategy for out-of-hospital refractory ventricular fibrillation. J Am Heart Assoc. 2016;5(6):e003732.
13. Yannopoulos D, Bartos JA, Raveendran G, et al. Coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest. J Am Coll Cardiol. 2017;70(9):1109-1117.
14. Sideris G, Magkoutis N, Sharma A, et al. Early coronary revascularization improves 24h survival and neurological function after ischemic cardiac arrest. A randomized animal study. Resuscitation. 2014;85(2):292-298.
15. Bartos JA, Voicu S, Matsuura T, et al. Role of epinephrine and extracorporeal membrane oxygenation in the management of ischemic refractory ventricular fibrillation. A randomized trial in pigs. JACC Basic Transl Sci. 2017;2(3):244-253.
16. Extracorporeal Life Support Organization (ELSO): ECLS registry report: International summary. ELSO: Ann Arbor, Mich., 2016.
17. Kagawa E, Dote K, Kato M, et al. Should we emergently revascularize occluded coronaries for cardiac arrest? Rapid-response extracorporeal membrane oxygenation and intra-arrest percutaneous coronary intervention. Circulation. 2012;126(13):1605-1613.
18. Maekawa K, Tanno K, Hase M, et al. Extracorporeal cardiopulmonary resuscitation for patients with out-of-hospital cardiac arrest of cardiac origin: A propensity-matched study and predictor analysis. Crit Care Med. 2013;41(5):1186-1196.
19. Wang CH, Chou NK, Becker LB, et al. Improved outcome of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest-A comparison with that for extracorporeal rescue for in-hospital cardiac arrest. Resuscitation. 2014;85(9):1219-1224
20. Sakamoto T, Morimura N, Nagao K, et al. Extracorporeal cardiopulmonary resuscitation versus conventional cardiopulmonary resuscitation in adults with out-of-hospital cardiac arrest: A prospective observational study. Resuscitation. 2014;85(6):762-768.
21. Lee JJ, Han SJ, Kim HS, et al. Out-of-hospital cardiac arrest patients treated with cardiopulmonary resuscitation using extracorporeal membrane oxygenation: Focus on survival rate and neurologic outcome. Scand J Trauma Resusc Emerg Med. 2016;24:74.
22. Kim SJ, Jung JS, Park JH, et al. An optimal transition time to extracorporeal cardiopulmonary resuscitation for predicting good neurological outcome in patients with out-of-hospital cardiac arrest: A propensity-matched study. Crit Care. 2014;18(5):535.
23. Avalli L, Maggioni E, Formica F, et al. Favourable survival of in-hospital compared to out-of-hospital refractory cardiac arrest patients treated with extracorporeal membrane oxygenation: An Italian tertiary care centre experience. Resuscitation. 2012;83(5):579-583.
24. Haneya A, Philipp A, Diez C, et al. A 5-year experience with cardiopulmonary resuscitation using extracorporeal life support in non-postcardiotomy patients with cardiac arrest. Resuscitation. 2012;83(11):1331-1337.
25. Stub D, Bernard S, Pellegrino V, et al. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015;86:88-94.
26. Johnson NJ, Acker M, Hsu CH, et al. Extracorporeal life support as rescue strategy for out-of-hospital and emergency department cardiac arrest. Resuscitation. 2014;85(11):1527-1532.
27. Schober A, Sterz F, Herkner H, et al. Emergency extracorporeal life support and ongoing resuscitation: a retrospective comparison for refractory out-of-hospital cardiac arrest. Emerg Med J. 2017;34(5):277-281.
28. Leick J, Liebetrau C, Szardien S, et al. Door-to-implantation time of extracorporeal life support systems predicts mortality in patients with out-of-hospital cardiac arrest. Clin Res Cardiol. 2013;102(9):661-669.
29. Fjølner J, Greisen J, Jorgensen MR, et al. Extracorporeal cardiopulmonary resuscitation after out-of-hospital cardiac arrest in a Danish health region. Acta Anaesthesiol Scand. 2017;61(2):176-185.
30. Pozzi M, Koffel C, Armoiry X, et al. Extracorporeal life support for refractory out-of-hospital cardiac arrest: Should we still fight for? A single-centre, 5-year experience. Int J Cardiol. 2016;204:70-76.
31. Lamhaut L, Hutin A, Puymirat E, et al. A pre-hospital extracorporeal cardio pulmonary resuscitation (ECPR) strategy for treatment of refractory out hospital cardiac arrest: an observational study and propensity analysis. Resuscitation. 2017;109-117.
32. Yannopoulos D, Bartos JA, Raveendran G, et al. Burden of coronary artery disease in patients with out-of-hospital refractory ventricular fibrillation cardiac arrest. J Am Coll Cardiol. 2017 (accepted manuscript.)
33. Tonna JE, Selzman CH, Mallin MP, et al. Development and implementation of a comprehensive, multidisciplinary emergency department extracorporeal membrane oxygenation program. Ann Emerg Med. 2017;70(1):32-40.
34. Elmer J, Rittenberger JC, Coppler PJ, et al. Long-term survival benefit from treatment at a specialty center after cardiac arrest. Resuscitation. 2016;108:48-53.
35. Callaway CW, Schmicker R, Kampmeyer M, et al. Receiving hospital characteristics associated with survival after out-of-hospital cardiac arrest. Resuscitation. 2010;81(5):524-529.
36. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 Suppl 2):S465-S482.
37. Sandroni C, D'Arrigo S, Callaway CW, et al. The rate of brain death and organ donation in patients resuscitated from cardiac arrest: a systematic review and meta-analysis. Intensive Care Med. 2016;42(11):1661-1671.
38. Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008;118(23):2452-2483.
39. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult advanced cardiovascular life support: 2015 American Heart Association American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 Suppl 2):S444-S464.