JC: ECPR for refractory OOHCA. St Emlyn’s

The use of Extracorporeal Cardiopulmonary Resuscitation (ECPR) has been considered by many resuscitationists as the next logical step in the management of cardiac arrest. This position is based on the understanding that when a patient goes into cardiac arrest many of our interventions are aimed at keeping the patient alive, but not at definitively treating the cause of the arrest. That can come later in a range of interventions ranging from PCI to rewarming and many things in between. Our aim in providing ALS interventions is to restore the circulation to a sufficient level such that the a patient can get the definitive treatment that they need. That’s why it’s called ‘Life Support’ and not definitive care. This was an epiphany for me some years ago when in conversation with our long time friend (and supporter of St Emlyn’s), Cliff Reid who described ALS in this way: ‘It’s something we do whilst figuring out how to really really treat what’s going on’. This is also the logic behind splitting leadership roles in any cardiac arrest one person leading the algorithm and another sorting out the underlying cause and any other complexities, that matches the idea of one person managing life support and the other working on definitive care.

ECPR offers a more sustained life support system that theoretically will allow a greater number of patients to reach the point where definitive care can take place. However, it’s not the easiest therapy to deliver in the out of hospital environment and whilst many services have demonstrated the feasibility of doing so (notably the French in Paris), the evidence base for its effectiveness has not been robust. In recent years a number of trials have rekindled interest in ECPR for OOHCA. The ARREST trial published in the Lancet showed a remarkable benefit for ECPR in selected cases (43% success vs 7% for standard therapies), but this was a small and very selective phase 2 trial. The question of ECPR in a less controlled system remained uncertain. This month we have a paper in the NEJM that is a randomised clinical trial of ECPR in the Netherlands. The abstract is below, but as always we strongly recommend you read the full paper yourself and come to your own conclusions.

The Paper

What kind of trial is this?

This is a randomised controlled trial which is generally the best option for testing an intervention. ECPR is certainly an intervention and so this is an appropriate trial design. The trial had an adaptive design with regard to sample size with interim analyses adjusting for outcomes in the first 40 patients.

Tell me about the patients.

Patient selection is key to any intervention trial. It’s important that we test in a population that might be able to benefit. This can be complex in cardiac arrest trials as there are obviously many pre-existing or circumstantial factors that can influence the possibility of success. Patients in this trial were considered to be in refractory arrest if their arrest had lasted more than 15 minutes. They included patients aged 17-70. Those patients with severe pre-existing comorbidities (such as severe heart failure, advanced cancer etc.) were excluded. This is a broader group of patients than in other studies/practice (particularly in regard to age).

Tell me about the intervention.

If a patient was deemed eligible they were transported to one of 10 cardiothoracic centres where ECPR was instituted on arrival. Extracorporeal CPR was performed with the use of Cardiohelp System and HLS Set Advanced 7.0 and 5.0 (Getinge). Post resus care was delivered according to local standard procedures.

The key point here is that ECPR was established in hospital and not in the out of hospital setting. This is the same as in the ARREST trial, but different to the French SAMU model where ECPR is commenced at scene. Clearly these two different options result in significant differences in the time to establishing ECPR, and likely differential effectiveness. This trial also included patients with >60mins prior to ECPR initiation which is longer than in other systems.

What about the outcomes?

The main outcome of the trial was survival with favourable neurological outcome at 30 days.

What about the results?

They enrolled 160 patients in the trial, but with exclusions this fell to 70 in the ECPR group and 64 in the conventional treatment group. The patients were reasonably similar in terms of baseline characteristics and time to hospital.

Cannulation was achieved in 46 of the patients randomised to the ECPR group (the 70 patients). Cannulation took an average of 20 minutes.

At the end point of this trial, 14/70 (20%) of the ECPR group had a favourable outcome as compared to 10/62 (16%) in the conventional group. This was not statistically significant (p=0.52), but the precision of this result is low with an Odds Ratio of 1.4 (0.5–3.5).

At three months the results were 12/68 (18%) vs. 9/63 (14%)

At six months the results were 14/70 (20% vs. 10/63 (16%)

So what does this trial tell us?

At face value this trial indicates that the anticipated improvement in outcomes did not occur, and some might say that this is a reason not to pursue ECPR. However, we should always be sceptical when looking at trials and there are a number of issues raised in the paper and on review that are worthy of thought (many described by the authors themselves in the discussion section).

This is still a small study, and a statistical effect would only be found if the clinical effect had been very large indeed. Remember that the authors anticipated a 22% increase in survival from a baseline of 8%. In the study the difference was 4% and the baseline as defined by conventional treatment was 16%. Thus the sample size calculation was arguably a little ambitious. The study was conducted in 10 centres which suggests low clinician exposure to this procedure in support of OOHCA. Other studies have had more experience and exposure to ECPR than here.

The setting is also interesting. It is likely that time to ECPR is a determinant of effectiveness. The average time to starting ECPR was 74 minutes (IQR 64-87 mins) which may be too long, and which is partly the function of having a hospital based ECPR service.

Patients were randomised at a point when there was still a significant amount of time before cannulation was attempted. This led to a number of patients reaching an outcome (ROSC or futility) before cannulation attempted. As a result of this and other factors such as technical difficulties, the intervention was only delivered in roughly a third of the patients randomised to the treatment arm (and three in the conventional arm), the apparent effectiveness (or otherwise) of ECPR may therefore have been reduced.

A number of commentators have pointed out that studies of this type are tests of a system just as much, if not more so, than of the specific intervention. Others, including the authors, have commented that the system was not fully matured at the time of the trial and with low levels of exposure and experience. Arguably it would be better to test the intervention in a system that is already familiar with the procedure.

Final thoughts

Some years ago in Virchester we looked at ECPR with an in-hospital cannulation model, but the practicalities of getting the right patients, to the right place, within the right time scale proved challenging. This paper rather supports those concerns. Perhaps it’s time to look at other systems that might provide more timely access and perhaps start ECPR in the out of hospital setting as the French and others have achieved. The bottom line is that there is more work to be done on this topic, with an emphasis on testing whether ‘systems’ can deliver an intervention, and thus whether it works in practice. There may well be (and I think there probably is) a system, and group of patients for whom ECPR will be of benefit, That system and patient group is yet to be fully defined.

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References

1. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. https://www.nejm.org/doi/full/10.1056/NEJMoa2204511
2. 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 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32338-2/fulltext