Episode 68- “Back to the Future?”: Vasopressin + steroids during cardiac arrest

Hello and welcome to Episode 68 of ER-Rx. In this “Fresh Fruit” series, I’ll discuss a recently-published meta-analysis entitled “Vasopressin and glucocorticoids for in-hospital cardiac arrest: a systematic review and meta-analysis of individual participant data.” This was published in the journal Resuscitation in December of 2021.

The authors were very timely in publishing this study. As we all know, the new-ish “Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (‘VAM-IHCA’) Study” was published in September of 2021. So, the authors of the meta-analysis I’ll be discussing today thought it would be a great idea to combine all of the literature to see if there truly is something to this med combination. Citing the fact that we don’t have the best evidence for any medication leading to clear long-term benefits during cardiac arrest, there’s been more and more interest in findings meds that do tangibly improve outcomes.

First, let’s talk about this particular combination of meds. Vasopressin is supposed to improve outcomes by vasoconstricting and increasing coronary perfusion pressure, but it never really panned out since studies showed no overall benefit in meaningful survival when combined with epi, or when used in place of epi. But still, replacing vasopressin makes some physiological sense, since endogenous vasopressin levels tend to be lower in patients who don’t survive cardiac arrest. Not to age myself, but when I was a student and early in my career, the ACLS guidelines actually recommended giving a one-time, 40-unit dose of vasopressin in place of the first or second dose of epi. But in 2015, the guidelines removed this recommendation since there was no added benefit of using it over epi or in combination with epi. The second component of the combo is a glucocorticoid. Glucocorticoids have been shown to increase rates of return of spontaneous circulation (ROSC) in animal cardiac arrest studies. Also, cortisol levels tend to be higher in patients who do survive cardiac arrest. Methylprednisolone specifically has been shown to enhance the heart’s ability to contract before and after a heart attack and also to increase the contractile function of peripheral arteries—both of which, as you can imagine, would be beneficial in cardiac arrest and post-resuscitation shock.

So, after digging through numerous databases, the authors ended up including only 3 randomized, placebo-controlled trials, and I’m going to discuss each of them briefly. One from 2009, one from 2013 (both of which were published by the same authors out of Greece) and the most recent 2021 “VAM-IHCA” study out of Denmark. As we go over these trials remember that survival to hospital discharge after an in-hospital cardiac arrest hovers around the 20% range. The 2009 study was a single-center trial in 100 consecutive patients that were given vasopressin 20 IU with epi 1 mg each CPR cycle for up to 5 doses. On the first cycle, 40 mg of methylprednisolone was also given. If patients assigned to the med combo group achieved ROSC, they were started on hydrocortisone 300 mg daily as a continuous infusion for a max of 7 days (27 patients). They found that ROSC rates (81% vs 52%, P= 0.003) and survival to hospital discharge rates (19% vs 4%, P= 0.02) were significantly higher in patients that received the med combo. The same authors again looked at this in 2013. This study included 268 consecutive patients and received they received the same combo of medications as in 2009, including the post-arrest hydrocortisone infusion. Patients given the combo again had significantly higher rates of ROSC (84% vs 66%, P= 0.005) and neurologically-favorable survival (14% vs 5%, P= 0.02). But the 2021 “VAM-IHCA” study out of Denmark was slightly different. It included 512 patients and they used the same med combo with the same doses, but only gave vasopressin for 4 cycles instead of 5, and they didn’t start that hydrocortisone infusion in the study patients who achieved ROSC. This study found significant increases in ROSC rates- an impressive 9.6% absolute increase (42% vs 33%, P=0.03)-, but not in survival to hospital discharge or favorable neurological outcome. This may be because of differences in post-cardiac arrest interventions and the fact that patients were older and had more unwitnessed arrests in this study compared to the other two Greek studies.

So, in terms of the meta-analysis itself, it included data from 869 patients, all of which came from the three studies we just reviewed. The pooled results leaned toward the med combo having significantly better outcomes for ROSC (OR 2.09; 95% CI 1.54-2.84), but not for survival at hospital discharge (OR 1.39, 95% CI 0.9-2.14) or favorable neurological outcome (OR 1.64, 95% CI 0.99-2.72). When they stratified the results in subgroup analyses by things like age, initial rhythm, time to giving the med combo, and the location of the arrest- there was no difference in outcomes. But, when they looked at time to med combo administration and treated it as a continuous variable, they found that the odds for survival to hospital discharge and a favorable neurological outcome decreased over time, which means that any potential benefit of giving the med combo goes away the longer you wait to give it.

In conclusion, a meta-analysis of three studies showed that the combo of methylprednisolone plus vasopressin may increase rates of ROSC, but did not show any effect on survival to hospital discharge or favorable neurological outcome. But overall, interpreting these results is very difficult. The meta-analysis may have been underpowered to detect differences given the lower number of patients included. The 2009 and 2013 studies showed improvements in all three measures of ROSC, survival to discharge, and favorable neurological outcome, but they were published by the same authors and at the same sites. The more recent 2021 study couldn’t replicate these results except for the improved ROSC rates. Remember that the 2009/2013 studies continued giving hydrocortisone 300 mg daily for up to 7 days for their patients, and this is potentially another factor in their improved survival rates. The most current ACLS guidelines from 2020 don’t recommend this combination, saying that the use of steroids during CPR is “of uncertain benefit”- but this was of course published before the most recent VAM-IHCA trail and this meta-analysis.

If you’re a cowboy excited and you’re really excited to try this, just make sure you do it as soon as possible during arrest, because it looks like the longer we wait, the less effective the combination is. And I guess you’d have to consider telling the ICU providers that we should start giving hydrocortisone 300 mg daily if the patient does achieve ROSC—so good luck with that. And don’t get too caught up on which steroid to use- it’s likely that hydrocortisone given at equivalent doses would have a similar effect. I do feel better that this is a safe intervention, with no differences in rates of hyperglycemia or hypernatremia, and it is relatively inexpensive (a 20 IU vasopressin vial costs $254.85, and methylprednisolone costs about $5). But still, don’t expect too much—like other meds we’ve discussed on this show including Zofran for nausea/vomiting (Episode 42), Vitamin C in sepsis (Episode 44), and Kcentra in patients with liver failure (Episode 64)—sometimes giving less meds is more.

As always, thank you so much for your time. Don’t forget to click on the show-notes, where you can find links to where you can leave me a review, subscribe to the pod, check out my references, and even support the show on BuyMeACoffee.com. With that said, I’d like to shout out a friend-of-the-pod ‘Wanderlust MD’ for hooking me up with 5 coffees- thank you so much! As long as I can help it, this show will be free to all listeners, so any little amount donated helps keep me going, pays the podcasting fees, and is used to buy prizes for periodic giveaways.