Does the Combination of Vasopressin and Methylprednisolone Administered During In-Hospital Cardiac Arrest Improve Return of Spontaneous Circulation?
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With this podcast, we recap innovative, practice changing studies in ten minutes or less. And remember, nothing here is medical advice; we just present the evidence and our (sometimes hot) takes.
Does the Addition of Vasopressin and Methylprednisolone Improve Outcomes in Patients with In-Hospital Cardiac Arrest?
Chest compressions, defibrillation, epinephrine, amiodarone…We all know these things as parts of our standard cardiac arrest algorithm. But is the standard algorithm good enough? Well in the US, only a quarter of patients who have an in hospital cardiac arrest make it to discharge. So clearly, we can do better…. but the question is how?
Well there were two very exciting, smaller studies about 10 years ago that showed the addition of vasopressin and methylprednisolone to standard care improved survival and neurologic outcomes in those with in hospital cardiac arrest….So why isn’t this part of the standard algorithm if we knew about this ten years ago? Well unfortunately, not much research goes into cardiac arrests and these smaller studies were never confirmed. The evidence was not felt to be high enough quality to include in guidelines.
The rationale for these drugs is that vasopressin causes vasoconstriction, increasing blood pressure and thus coronary perfusion. Studies have also shown that those who are successfully resuscitated have higher cortisol levels on average than those who don’t make it, so this led to the idea of just giving everyone some steroid. So, now we’ve got some researchers who’ve finally taken up the reins to help us answer the question of whether vasopressin and methylprednisolone should be incorporated into our standard ACLS guidelines.
So this week we’ve got a multi-center, randomized, double blind, placebo controlled trial of just over 500 adults with in hospital cardiac arrest in Denmark. In the treatment group, patients were given a dose of 40 milligrams of methylprednisolone and 20 units of vasopressin after the first dose of epinephrine. An additional 20 units of vasopressin was given after each subsequent epinephrine dose for a maximum of 4 total doses. The other group received a matching saline placebo.
The one notable exclusion criteria were those on ECMO or other mechanical circulatory support were not allowed in the trial.
The primary outcome was a sustained return of spontaneous circulation, but researchers also looked at survival and neurologic outcomes at 30 and 90 days after cardiac arrest. Baseline characteristics were similar between the two groups, and the mean age was 71 years old.
The researchers found that 42% of treatment group patients had successful return of spontaneous circulation compared to 33%in the placebo group. This was an absolute risk difference of 9% and was statistically significant. In this case, the number needed to treat is 11, meaning that 11 patients would have to be treated in order to achieve one additional return of spontaneous circulation.
This seems exciting, but when they looked at the data from day 30 and day 90 post cardiac arrest, they saw no improvement in survival or neurologic outcomes. In fact, survival was slightly but not significantly worse in the treatment group.
It’s funny, because you need to have return of spontaneous circulation in order to survive, so you’d think it would work as a proxy for 30- or 90-day survival, but clearly it doesn’t. So why didn’t this trial show the same promising results as previous smaller trials?
Well, there are a couple possible reasons. First, in previous trials, hydrocortisone was used which may be a more physiologic steroid. Second, in order to accurately reflect clinical practice, this trial allowed for drug administration by clinical staff rather than research staff as in previous trials. This may have resulted in a less timely administration of drug. It did appear that a small number of patients had a significant delay in drug administration which probably reflects normal clinical practice but may have affected outcomes. And third, the previous trials also had an overall younger cohort.
While over 500 patients were included, a good number ended up being excluded for various reasons, most commonly that they never received their first dose of epinephrine. This might limit how generalizable the study is. But maybe, the most important weakness of the study was the power. They powered it adequately for their primary outcome but had nowhere near enough statistical power to detect differences in the 30- and 90-day survival and neurologic outcomes. This is a shame, because if you really want to determine if something should be standard of care in guidelines, the 30-day survival and neurologic outcomes are the most crucial aspect.
So, while the intervention improved short term outcomes, the effectiveness in the longer term is still up for debate. A positive effect on return of spontaneous circulation is great, but in order for this to become standard practice, we’d like to see those 30- and 90-day outcomes improved as well.
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