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Journal Club by CanadiEM E05: The ARREST trial and ECMO programs

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Join us and our expert guest Dr. James Gould as we discuss ECMO and mature ECMO programs, appraise the ARREST trial and consider the future of cardiac arrest care. Today’s hosts are Jayneel Limbachia, Dakoda Herman, and Jake Domm.

Expert Guest: Dr. James Gould is a father of 3, emergency medicine physician and assistant professor at QEII Health Sciences Center and Dalhousie University in Halifax, Nova Scotia, with a special interest in resuscitation and ECMO delivery.

What is ECMO?

Extracorporeal membrane oxygenation. Blood is removed, oxygenated, and pumped back into the body. ECMO can be used to bypass the lungs and oxygenate blood in V-V ECMO, or bypass the heart and lungs in V-A ECMO. In the context of cardiac arrest, when V-A ECMO is used it’s referred to as ECPR, or extracorporeal cardiopulmonary resuscitation.

ECMO-facilitated resuscitation requires a considerable amount of coordination to get the patient to the intervention quickly. Our experience is to have a team leading cardiac arrest care, another team putting the patient on ECMO, and someone leading the coordination. This can take place in the ED, pre-hospital, or in the cath lab. Pre-hospital may ultimately be the most time effective way, but not always possible. For example, a group out of Paris [2] essentially has a mobile ICU unit providing ECPR 365 days a year in the pre-hospital setting.

What are the roles of ECMO and when should it be used in resuscitation?

V-V ECMO: patients with sick lungs, i.e. ARDS

V-A ECMO: patients with sick hearts, i.e. cardiogenic shock or cardiac arrest.

The goal of ECMO in cardiac arrest is essentially buying time by creating artificial circulation and producing some coronary flow in order to get patients to the cath lab to intervene.

ECMO is often thought of as a last resort, but more literature will likely be coming out in terms of optimal timing and patient selection. In general, ECMO is used as a bridge to buy time, for example in cardiac arrest due to coronary lesions where ECMO is used to bridge patients to the cath lab, or hypothermia bridging until the patient is warmed, or bridging until toxic effects wear off in the case of certain cardiotoxins.

The golden hour is key, because we really want to minimize low flow time and the time patients are receiving CPR before we get them on ECMO.

ARREST Trial Overview

This trial was a single-center RCT, in a center that already had a mature ECMO program, and they compared early-initiated, in-hospital ECMO facilitated-resuscitation versus the control arm which was standard ACLS treatment. They looked at this in patients who had out of hospital cardiac arrest and refractory V fib who had an estimated transfer time to the emergency department of less than 30 minutes. The outcomes they looked at were survival to hospital discharge, safety, as well as survival and functional outcomes at 3 and 6 months. The trial itself was terminated by the data safety monitoring board after 30 patients in total were enrolled because they observed 1/15 patients in the ACLS arm surviving to discharge compared to 6/14 in the ECMO arm.

(1) PICO

o   P – This study included all consecutive adults (presumed or known to be 18–75 years old) with an initial OHCA rhythm of ventricular fibrillation or pulseless ventricular tachycardia, no ROSC after three defibrillation shocks, body morphology able to accommodate a Lund University Cardiopulmonary Assist System, and an estimated transfer time to the emergency department shorter than 30 min. Exclusion criteria included valid do not resuscitate orders; blunt, penetrating, or burn-related injury; drowning; known overdose; known pregnancy; being a prisoner; being a nursing home resident; presence of an opt-out study bracelet; unavailability of the catheterisation laboratory; terminal cancer; absolute contraindications to emergent angiography; contrast allergies; and active gastrointestinal or internal bleeding. Sustainable ROSC within the first three shocks was an exclusionary criterion from the study.

o   I – Included patients were randomly assigned to either standard ACLS resuscitation or early ECMO-facilitated resuscitation.

o   In the early ECMO-facilitated resuscitation group, patients gained immediate access to the cardiac catheterisation laboratory regardless of presence or absence of pulses on hospital arrival. In the catheterisation laboratory, patients undergoing cardiopulmonary resuscitation had arterial blood gas collected and, if resuscitation discontinuation criteria were met (two or more of the following: end-tidal CO2 <10 mm Hg, PaO2 <50 mm Hg, or oxygen saturation <85%, and lactic acid 18 mmol/L), all further efforts were terminated and the patient was declared dead. If not, peripheral veno-arterial ECMO support was initiated and an angiogram immediately done with revascularisation as clinically indicated. If patients had a pulse and were stable upon arrival, they were treated with an angiogram or angioplasty and circulatory support as required.

o   All patients who survived to hospital admission were treated in a dedicated cardiac intensive care unit (ICU) by a specialised cardiology critical care team. Postresuscitation care was not protocolised but followed local standard of care for both groups. This standard of care includes 24 h of therapeutic hypothermia (target 34°C for 24 h), minimisation of vasopressor support with optimisation of ECMO flow, no neuroprognostication for at least 72 h after cardiac arrest, head CT on admission and at day 3 for all patients, and continuous electroencephalogram monitoring until awakening. Using standard scales, masked certified research nurses obtained cerebral performance category and modified Rankin scores of patients during an interview at hospital discharge and 3 months and 6 months after discharge.

o   C – In the standard ACLS resuscitation group, patients stayed in the emergency department under care of emergency physicians. In patients without pulses, the protocol dictated that the emergency department team continued treatment for at least 15 min after arrival to the department or for at least 60 min after the 911 call. Afterwards, if the patient did not achieve ROSC, continued resuscitation or declaration of death was at the emergency physician’s discretion. If the patient arrived with pulses or achieved ROSC at any point during resuscitation, the emergency physician transferred the patient for angiography, angioplasty, and circulatory support as needed per clinical protocol.

o   O – The primary outcome was survival to hospital discharge.

o   Secondary endpoints were survival and functionally favourable status at hospital discharge and at 3 and 6 months after hospital discharge, defined as a modified Rankin score of 3 or lower (range from 0 [no symptoms] to 6 [death]) and a cerebral performance category scale of 2 or lower (range from 1 [good cerebral performance] to 5 [death]).

(2) Was the assignment of patients to treatments randomized?

 Included patients were randomly assigned to either standard ACLS resuscitation or early ECMO-facilitated resuscitation. On hospital arrival, at least one member of the research team was available to verify inclusion or exclusion criteria and eligibility for the study, and they were responsible for enrolment and assignment of patients to the groups. Randomisation to one of the two standards of care was immediately done by use of a secure schedule generated by the Statistical Data and Coordinating Center using permuted blocks with randomly varying block sizes. The initial randomisation schedule was generated with use of a standard random number generator in R, with random permutations in blocks of two, four, and six to ensure approximate balance between the two groups and initially equal probability of assignment to either group. Allocation concealment was accomplished with a randomisation schedule with physical masking that required scratching off a completely opaque layer to determine assignment.

(3) Were the groups similar at the start of the trial?

Yes, as you can see in Table 1, groups were similar at the start of the trial.

(4) Aside from the allocated treatment, were groups treated equally?

 Yes, the authors provide a table summarizing all treatments and procedures according to intention-to-treat. There are some interventions that occurred more commonly in the ECMO-assisted arm of the study; however this is largely owing to the fact that more patients in this arm survived to have these interventions instituted.

(5) Were all patients who entered the trial accounted for? And were they analyzed in the groups to which they were randomized?

All patients who entered the trial were accounted for except for one participant who withdrew consent from participating after day 3. The loss to followup is therefore minimal. Nonetheless, they conducted an intention to treat analysis, removing any bias and ensured the patients were analyzed in the groups to which they were randomized. 

(6) Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?

The primary outcome of survival to hospital discharge is objective and emergency teams, investigators, critical care team and outcome assessors were masked to the group allocation. Patients were blinded to which treatment/intervention they were receiving.  

(7) What were the results and How large was the treatment effect?

Important to keep in mind that this study was done in a high performance, world class ECMO program that at this point, could be considered the gold standard. That’s not to discourage other centers, but to illustrate the potential of ECMO programs if used in the right setting, with the right providers, to the right patients, in the right time limit.

What outcomes are important to us? Is it survival, or functional outcomes? Looking at the trial, they followed patients at hospital discharge, 3 months and 6 months and actually showed favorable neurological outcomes!

What is posterior probability? In short, it’s not a p-value. It is the conditional probability, otherwise known as an updated or revised probability of something occurring given the new evidence found in the trial. In this trial, they calculate posterior probability after each 30 patients enrolled to determine the conditional probability that ECMO is superior to ACLS given the data they have established. This is a form of Bayesian statistics, not unlike the decision making that you do every day in the emergency department. You run a test, collect more data, and revise your probability of whether a patient has a particular diagnosis. In this study, more specifically, they used non-informative, neutral prior distributions and calculated posterior probabilities using the 43% survival to discharge in ECMO and 7% survival in ACLS observed in the first 30 patients. They found that there was a posterior probability that ECMO is superior to ACLS in this population of 0.9861.

(8) How precise was the estimate of the treatment effect?

In this trial they report credible intervals, which although serves a similar purpose as confidence intervals summarizing the uncertainty related to the unknown parameter you are trying to estimate, they are less complex. In fact, credible intervals are just saying “given the observed data, the effect has 95% probability of falling within this range”. This is probably what most of us consider confidence intervals to be, although that’s not true because confidence intervals are stating (in the case of a 95% confidence level) “95% of confidence intervals calculated from the data using the 95% confidence level will contain the parameter.” In our case, they used a 95% credible interval and the intervals were 1.6–30.2% survival for the ACLS arm and 21.3–67.7% for the ECMO arm, with a risk difference of 36.2%, and credible interval 3.7–59.2%. So yes, the intervals are wide, yes the intervals of the two groups cross each other, yes we probably would have liked more participants to narrow those intervals in a bit. But we don’t have that data! The posterior probability that ECMO is superior to ACLS was higher than their threshold set at 0.9861 after the first round of 30 patients, so the study was stopped.

Is ECMO-facilitated resuscitation financially responsible?

ECMO is expensive and a finite resource. But, ECMO is considered a very good value for quality adjusted life years, particularly in younger patients predicted to have good neurological criteria [3]. Also, with ECMO if you choose the appropriate patients, you generally see whether it is having an effect quickly and can reevaluate its use, therefore the device isn’t being tied up for weeks on end.

What does it mean to be a “mature ECMO program?”

The better question is, “how do you start?” Recognize there are many people involved in ECMO programs. In our department there are RTs, nursing staff, cardiac surgeons, perfusionist, emergency physicians, the ICU team and the patient’s family. Good relationships between services are vital. Then there’s the easy stuff, like ECMO infrastructure including the equipment, space, and a place to go once patients are on ECMO, like an ICU. Then there are the details separating a mature program from the rest. Having a fine-tuned process practiced through simulation, regular debriefing, improvement, and detailed criteria for patient selection.

Highlighting simulation, think about how in emergency medicine we are expected to be able to perform these processes often without regular practise. How crazy is that! Would an athlete be expected to perform without regular practise? No. The programs that practise together, through regular simulation and figure out the small details end up performing well.

Is it feasible to have transfer times of <30mins and 911 call to ECMO initiation of <60mins?

A time requirement of ECMO initiation within 60 minutes outlined in the ARREST trial sounds like a tight timeline, and it is, requiring efficient coordinated efforts, but it is reproducible as was shown in a Canada-wide study [4], particularly after implementing a process with clear criteria and a motivated team [5]. It’s important to be honest about what our current system can provide. Does our center have in-house services required for ECMO initiation over night or on weekends? Is it possible to get everyone to the hospital and have ECMO initiated within 60 minutes? If the answer is no, then ECMO shouldn’t be offered during those times, or the system needs to change to have ECMO initiated within 60 minutes. The EROCA trial [6] looked at ECPR feasibility and showed 5/12 enrolled participants met criteria for 30-minute transport times, and 3/5 had ECMO initiated within 30 minutes of ED arrival. We need to think about how broadly are we going to travel to bring patients to the hospital? Our system places decision making in the hands of EMS to decide if the patient should be transported for ECMO, because they are the ones that know the situation and when they can get to hospital.

A time requirement of 30-minute transport time may be less important than the overall requirement of ECMO initiation within 60 minutes. Focusing on transport time may be less important if once a patient arrives to the ED they can be cannulated and have ECMO initiated in under 10 minutes. Furthermore, having someone transported to hospital from the pre-hospital environment is not without risks for the EMS provider on scene. Have we ever had to do compressions while standing up in the back of an ambulance while our partner drives through a snowstorm? Mechanical CPR devices, such as the LUCAS device, are becoming more ubiquitous and may help with provider safety.

Is the ARREST trial practise changing?

At the center performing this study, by Dr. Yannopoulos et al, the question is not whether the results have internal validity, or rather, can we believe them, but instead the question is whether we can apply them to our site. The methodology and evidence is convincing of these results being true and having more patients would likely only narrow the result precision, although without having more patients we cannot be certain of that. However, the better question is whether this trial has external validity, or, how well we can apply these results to other settings. As discussed earlier, the ARREST trial was performed by a mature ECMO program and cannot necessarily be applied to new ECMO programs, but instead provides a guide of what can be feasible.

What is the future of ECMO-faciliated resuscitation?

The technology will get safer with fewer complications, become more accessible, and easier to implement. It may be an intervention that EM physicians can provide in the ED or even prehospital setting but will likely always be a collaborative effort. If shown possible and safe, having a broader scope of who can initiate ECMO will allow it to be utilized more often in more environments.

References:

Yannopoulos D, Bartos J, Raveendran G, Walser E, Connett J, Murray TA, Collins G, Zhang L, Kalra R, Kosmopoulos M, John R, Shaffer A, Frascone RJ, Wesley K, Conterato M, Biros M, Tolar J, Aufderheide TP. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet. 2020 Dec 5;396(10265):1807-1816. doi: 10.1016/S0140-6736(20)32338-2. Epub 2020 Nov 13. PMID: 33197396; PMCID: PMC7856571.

Lamhaut L, Hutin A, Puymirat E, Jouan J, Raphalen JH, Jouffroy R, Jaffry M, Dagron C, An K, Dumas F, Marijon E, Bougouin W, Tourtier JP, Baud F, Jouven X, Danchin N, Spaulding C, Carli P. 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 Aug;117:109-117. doi: 10.1016/j.resuscitation.2017.04.014. Epub 2017 Apr 14. PMID: 28414164.

Matsuoka Y, Goto R, Atsumi T, Morimura N, Nagao K, Tahara Y, Asai Y, Yokota H, Ariyoshi K, Yamamoto Y, Sakamoto T; SAVE-J Study Group. Cost-effectiveness of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: A multi-centre prospective cohort study. Resuscitation. 2020 Dec;157:32-38. doi: 10.1016/j.resuscitation.2020.10.009. Epub 2020 Oct 17. PMID: 33080369.

Grunau B, Shemie SD, Wilson LC, Dainty KN, Nagpal D, Hornby L, Lamarche Y, van Diepen S, Kanji HD, Gould J, Saczkowski R, Brooks SC. Current Use, Capacity, and Perceived Barriers to the Use of Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest in Canada. CJC Open. 2020 Nov 13;3(3):327-336. doi: 10.1016/j.cjco.2020.11.005. PMID: 33778449; PMCID: PMC7985000.

Sun T, Guy A, Sidhu A, Finlayson G, Grunau B, Ding L, Harle S, Dewar L, Cook R, Kanji HD. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for emergency cardiac support. J Crit Care. 2018 Apr;44:31-38. doi: 10.1016/j.jcrc.2017.10.011. Epub 2017 Oct 12. PMID: 29040883.

Hsu CH, Meurer WJ, Domeier R, Fowler J, Whitmore SP, Bassin BS, Gunnerson KJ, Haft JW, Lynch WR, Nallamothu BK, Havey RA, Kidwell KM, Stacey WC, Silbergleit R, Bartlett RH, Neumar RW. Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport. Ann Emerg Med. 2021 Jul;78(1):92-101. doi: 10.1016/j.annemergmed.2020.11.011. Epub 2021 Feb 1. PMID: 33541748; PMCID: PMC8238799.

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Jakob Domm

Jakob Domm

Jake is a 3rd year medical student at Dalhousie Medical School. He has interests in EM and research, completing his MSc. at Guelph University in pathobiology. Outside of medicine, Jake enjoys crossfitting with his wife and hiking with their dog.
Jakob Domm
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