After years of waiting, PARAMEDIC 2, the large RCT of epinephrine for out of hospital cardiac arrest, has finally been published. So we can now definitively say that epinephrine is harmful. Wait, maybe it helps? Can a positive study demonstrate harm? Maybe this EBM stuff isn’t so easy after all…
PARAMEDIC 2 is a multicenter, randomized, double-blind, placebo controlled trial
Patients: They included all adult patients with out of hospital cardiac arrest for which advanced life support was provided by trial-trained paramedics.
- Excluded: Patients younger than 16 years old, known or suspected pregnancy, cardiac arrest from anaphylaxis or asthma, or administration of epinephrine before the arrival of the trial trained paramedics.
Intervention: Epinephrine 1 mg IV push every 3-5 minutes.
Comparison: Placebo (saline).
Outcome: The primary outcome was 30 day survival.
- Secondary outcomes included rate of survival until hospital admission, the lengths of stay in the hospital and ICU, the rates of survival at hospital discharge and at 3 months, and the neurologic outcomes at hospital discharge and at 3 months.
They enrolled 8014 patients. (10,623 were screened, with the majority of exclusions occuring because epinephrine had been given before trial paramedics arrived, or because the patient achieved ROSC before randomization.)
For the primary outcome of 30 day survival, the epinephrine group had a small but statistically significant increase in survival: 3.2% vs 2.4% (OR 1.39; 95% CI 1.06-1.82, p=0.018). The fragility index for this result is 6.
There was no difference in neurologically favourable survival (modified Rankin score 3 or less) at hospital discharge, or at 3 months: 2.1% vs 1.6% (OR 1.31; 95% CI 0.94 – 1.82).
A lot more patients had return of spontaneous circulation in the field with epinephrine (36.3% vs 11.7%). More patients were also admitted to hospital with epinephrine (23.8% vs 8.0%).
My thoughts on PARAMEDIC 2
I have to admit, I was excited for the release of this trial. There has never been convincing evidence that medications help cardiac arrest patients. Observational data has repeatedly shown increased rates of ROSC with epinephrine, but no benefit in terms of neurologically intact survival. (Loomba 2015) The classic OPALS trial demonstrated no improvement in survival with the introduction of advanced life support paramedics. (Stiell 2004) And there was the fantastic prior RCT on this topic which demonstrated no benefit, but unfortunately had enrollment issues and ended up under-powered. (Jacobs 2011) I have always worried that epinephrine might be hurting my patients. I was excited for this trial to be published, so we would finally have a definitive answer. That was my mistake. I should have realized that there is no such thing as a perfect trial. There are always caveats. We don’t get definitive answers.
The big caveat that will drive most opposing views on this trial is the presence of two different but important outcomes: survival, and survival with good neurologic function. That is the crux of the issue, but before we dive in, let’s tackle a few smaller issues.
First, the survival rate was pretty abysmal here. Only 3.2% of the epinephrine group was alive at 30 days. Many communities have much higher survival rates than that (although I think some also have lower rates of survival). In cardiac arrest, we have two groups of patients: dead and only mostly dead. Some patients will not recover no matter what we do. If these patients are over-represented in a trial, they could hide a true benefit in the small subset of patients who actually have a chance of surviving. (EDIT: 615 patients were excluded because of ROSC before the trial paramedics arrived. Therefore, selection bias probably contributes to the low survival seen.)
A related issue is the length of time it took to deliver epinephrine. We know that patients who are likely to achieve ROSC are likely to have it happen early in their resuscitation. Early defibrillation is clearly helpful. If it is going to work, epinephrine probably also needs to be given early. Although response times were pretty good in this trial (6 minutes), the time until the first dose of study drug was very long (about 22 minutes). By 22 minutes, it might simply be too late. (This is not a comment at all on the paramedics here. Working in the prehospital environment is incredibly difficult, and a large number of factors can contribute to delay).
The dose of epinephrine will also likely be discussed. Is 1mg really the best dose? I have always found it weird that I can give a 1 mg IV push of epinephrine to a patient without a pulse, but if I wait just 30 seconds and the patient regains a pulse, that same dose would be considered negligent. Scott Weingart has spoken at length about titrating epinephrine based on arterial line blood pressures, but most of us are still treating empirically. Although people will want to discuss dose, that isn’t what this trial was about.
I could discuss a number of issues with the modified Rankin score. A cutoff of 2 instead of 3 might be a better representation of the kind of outcomes we would all want. There are a number of ways this data could be dissected or presented, but I have previously discussed how subjective or inaccurate this score can be. But the thing that bothers me the most might seem like a really small point: the use a logarithmic scale when displaying these results, which completely distorts the outcomes. This chart will be widely spread, but it is very misleading.
But let’s get back to the real issue with this trial: what outcome should we care about? The primary outcome of this trial was 30 day mortality, and epinephrine was better. Sounds pretty simple. We should use epinephrine. Unfortunately, increasing quantity of life does not necessarily increase quality of life, and our patients actually care more about quality than quantity. Therefore, the fact that epinephrine failed to improve survival with good neurologic outcome seems to make this a negative trial.
I would argue that any intervention that increases survival, but doesn’t increase survival with good neurologic outcomes, is clearly harmful. That combination means that patients “saved” are left with poor functional outcomes and a quality of life that might not be appreciated.
And there are further harms. Epinephrine increased ROSC. It also increased admissions to hospital. At face value, those sound like good outcomes, but when you consider the fact that these patients were not going to walk out of the hospital, I think this is clearly harmful. Leaving aside the added costs, I don’t know any person who wants to spend the final days of their life in an ICU. We are willing to tolerate ICU care if there is hope. If there is a chance at survival. But epinephrine seems to fill our ICUs, and subject our patients to aggressive care, without any real chance that the patients will go home.
Optimists will often argue with me on this point. “Let’s just get these patients into the ICU”, they say, “and then we can focus on other interventions like TTM or ECMO to improve their neurologic outcomes”. It is true that we will never be able to improve outcomes if we give up on our patients too early. I don’t want to be overly pessimistic. But for now, none of those downstream interventions have shown any benefit. I think it is a mistake to allow our optimism for the future to translate into harm for our current patients.
My comments thus far have all assumed that epinephrine does not improve survival with good neurologic outcomes. If that is the case, I would argue very strongly that epinephrine is harmful and should be abandoned. Unfortunately, if we take a close look at the data, things get a little more complicated.
In the epinephrine group, 2.2% of patients survived to hospital discharge with a favourable neurologic outcome. In the placebo group, it was 1.9%. Although this was not a statistically significant difference, the point estimate is still higher in the epinephrine group. At 3 months, the results are similar (2.1% vs 1.6%). What stands out to me are the odds ratios. The odds ratio for 30 day survival was 1.39. The odds ratio for a good neurologic outcome at 3 months was 1.31. Those numbers are very similar. The absolute numbers are tiny, but that might be primarily driven by the tiny number of survivors over all. If those same odds ratios held true in a population with a 10% baseline survival rate, the absolutely differences might actually be clinically important.
Ultimately, the key question here is one of values, not of statistics or methodology. It seems pretty clear that epinephrine will result in more return of spontaneous circulation, and more admissions to hospital. It probably increases overall survival, but that survival might come with a significantly decreased quality of life.
If we take the numbers here at face value, and forget statistics for a minute, for every 1000 out of hospital cardiac arrests, the use of epinephrine will result in 246 extra cases of ROSC, 158 extra admissions to hospital, and 8 extra survivors at 30 days. Of those 8 extra survivors, 3 would have a good neurologic outcome and 5 would have a bad outcome.
Those are the numbers, but I am not sure what they mean. Are the 3 good neurologic outcomes worth the 5 bad outcomes? Are they worth the 158 extra ICU admissions? Does the benefit outweigh the harm?
I give a lot of credit to these authors. They provide us with one of the best discussion sections I have ever read. They talked to patients and the public before starting this trial to determine what outcomes were important. They note that a number needed to treat of 112 is below what is generally considered to be the minimal clinically important outcome. They tell us that patients care more about neurologic outcomes than survival alone. They note that “patients may be less willing to accept burdensome treatments if the chances of recovery are small or the risk of survival with an impaired neurologic outcome is high.”
These are the important questions. In the coming days and months, physicians are going to spend a lot of time debating the implications of this trial. No amount of debate is going to provide us with clarity. These are not questions that should be left in the hands of clinicians. These are questions that we need to address as a society. What counts as a good outcome? How small a difference are we willing to chase? And what costs are we willing to pay? Where does organ donation fit into this conversation? We don’t need another RCT – we need research that involves the public and endeavours to answer these very difficult questions.
I think people will use PARAMEDIC 2 to support their existing belief, whatever that is. This data demonstrates that epinephrine has, at best, a very minimal impact on patient oriented outcomes. It is not clear that the benefit outweighs the harm.
UPDATE: Since this post on PARAMEDIC 2, I have completed a more thorough review of the literature on epinephrine for out of hospital cardiac arrest, which can be found here.
JC: Does Epinephrine work in Cardiac Arrest on St. Emlyn’s
Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011; 82(9):1138-43. [pubmed]
Loomba RS, Nijhawan K, Aggarwal S, Arora RR. Increased return of spontaneous circulation at the expense of neurologic outcomes: Is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? Journal of critical care. 2015; 30(6):1376-81. [pubmed]
Stiell IG, Wells GA, Field B, et al. Advanced cardiac life support in out-of-hospital cardiac arrest. The New England journal of medicine. 2004; 351(7):647-56. [pubmed]