Vasopressin & Methylprednisolone: Time to Add Them to ACLS Protocols?

My love for ACLS goes back far in my career. I fondly recall taking an ACLS/BLS course after completing medical school and prior to starting residency. It was a small class, just a couple students. The instructor was a charismatic firefighter (who I remain friends with to this day) who noted that I was particularly excited about the whole ACLS thing. Needless to say, he offered me a job teaching for his company, MedTrain, and I worked with him until starting residency. Around this time, the 2010 AHA Guidelines had just been published. Vasopressin had been removed from said guidelines. Obviously, using both vasopressin and methylprednisolone/glucocorticoids in ACLS is something new to me although being studied in the past.

When I started residency, running codes was a process that I already had a year of experience in training people how to do. It was always entertaining, given that I was a certified instructor, to see certain upper levels fumble around with the ACLS cards in their pocket while yelling at staff, losing control of the room. Today, I serve as a co-physician champion for the Code Blue/Rapid Response Team Committee and representative for my hospital. Word of advice: sometimes it’s better to share responsibilities with your friends than tackle the whole project on your own. Especially when some meetings take place at noon when you’re working nights.

Running Code Blue Scenarios Today

Today, I have simplified how I run codes. I remain an adrenaline junkie and try to be the first one there. During the code, I also try my best to instruct constructively while the code is ongoing. People tell me the love when I show up to codes because everything is smooth, but they might be lying to my face. Running codes are generally straightforward, although how I do it is beyond the scope of this post. We seem to have an obsession with giving epinephrine, which we know is not always helpful.

To not create too much chaos, a recent trick I was taught was to provide epinephrine at every other pulse check. This means the patient will receive the epinephrine at 4 minute intervals. Smack in the middle of the 3-5 minute intervals noted on the AHA guidelines. Now it seems that a curveball has been thrown my way and I need to fight my urge to not change what I do.

JAMA RCT on Vasopressin and Methylprednisolone (Glucocorticoids)

In September of 2021, a trial in JAMA (which is NOT FREE for you to download) showed up in my mailbox. The non-sexy name of the trial is the VAM-IHCA study. This stands for Vasopressin And Methylprednisolone for In-Hospital Cardiac Arrest. The first sentence of the paper states that 300,000 patients suffer from in-hospital cardiac arrest in the US each year. Therefore, JAMA decided to put this paper behind a paywall to allow fewer people to access it. Angry commentary now over. I have to tip my hat to the authors here because I have contemplated how challenging it is to recruit patients to an ACLS study. The ended up with 501 patients when it was all said and done. Kudos.

They way they did it, in case any of us want to perform a trial like this, was after “Oral and subsequent written informed consent was temporarily obtained from a physician independent of the trial until the patient regained capacity or a surrogate became available according to Danish legislation”. I am unsure whether this is possible in the United States.

Dose of Vasopressin and Methylprednisolone (Glucocorticoids)

Let us say we want to do this. We have to know the doses provided in the trial to defend ourselves with data. In the study, they used 40mg of methylprednisolone and 20IU of vasopressin IV/IO as soon as possible after the first dose of epinephrine. Then, they provided additional doses of vasopressin at 20IU after each epinephrine dose up to a total of 4 doses. This would be a total of 80IU of vasopressin in total. It does not seem as if the patients received additional methylprednisolone.

What were the results on the VAM-IHCA Study?

The primary outcome was return of spontaneous circulation (ROSC). I completely agree with this being the primary outcome for this study. In the vasopressin and methylprednisolone group, 42% of patients achieved ROSC. In the control group, 33% achieved ROSC. If we plug this into our nifty number needed to treat calculator, we find that it is just 11.1 patients. This is not bad. Another way to look at these results is that there was an “absolute increase of 9.6% in ROSC”.

The sample size was calculated for the primary outcome. Some would criticize that there’s no evidence in improvements in survival but those folks are being academically dishonest. After that, that is a secondary outcome and the study is not powered for that outcome.

One of the more telling results from the subgroup analysis, figure 2, is that the earlier the patients receive the combination of epinephrine, vasopressin, and methylprednisolone, the better. If it is provided in 8 minutes or less, there is a statistically significant improvement in ROSC compared to just epinephrine. It seems obvious that the earlier it is provided the better, but it is nice to see on paper.

The authors were gracious in their limitations, as is appropriate. The editorial by Haukoos et al. does the typical chest thumping of “we need more data before changing practices”. That’s not an actual quote but my commentary on their commentary. I’m guilty of this as well but it’s easy to criticize a study when you’re not the one doing it.

A systematic review and meta-analysis on vasopressin and methylprednisolone already?

Thankfully, this paper by Holmberg et al. in Resuscitation is free for you to download. Yes, I am throwing shade at JAMA for hiding the other paper behind the paywall. After the authors performed their analyses, the conclusion after looking at three trials is that the combination of methylprednisolone and vasopressin improves ROSC in patient who suffer in-hospital cardiac arrest. The confidence intervals are honestly rather wide. Other outcomes such as survival to hospital discharge and neurologic outcome remain unknown. They concluded that “larger trials are needed to determine whether there is an effect on longer-term survival and favorable neurological outcome.”

What am I going to do next?

I will be discussing the results of this trial, as well as the subsequent meta-analysis with my team to make sure that I am not overlooking something. A particular issue is changing the way we currently do things. Although this would affect a limited amount of clinicians at my facility, this could be a larger issue at academic institutions where numerous ED and IM residents are the ones who run the codes. In addition, nursing has to be looped in and significant education will need to take place. Also, code carts and jump bags will need to be stocked appropriately.

My approach is a more democratic one and I will speak with multiple people prior to upending the way we do things. Change for the sake of change is not always for the best. Of course, none of this is medical advice. If you’re stuck in a code without access, should you place an IO or an IV? Check out this post to find out.

ADDENDUM 2/5/22

On 2/2/22 there was another systematic review and meta-analysis of randomized-controlled trials published that looked at methylprednisolone and vasopressin in cardiac arrest. This time in the Journal of Intensive Care. Coming to similar conclusions, the authors stated that methylprednisolone and vasopressin “may have beneficial effects in terms of the ROSC, renal and circulatory failure free days, and MAP”. We have to add that they included epinephrine to the mix which was expected. They looked at two studied for this meta-analysis versus a larger amount in the previous paper cited above.

Citations on Vasopressin and Glucocorticoids

Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, Darling S, Zwisler ST, Fisker S, Schmidt JC, Kirkegaard H, Grejs AM, Rossau JRG, Larsen JM, Rasmussen BS, Riddersholm S, Iversen K, Schultz M, Nielsen JL, Løfgren B, Lauridsen KG, Sølling C, Pælestik K, Kjærgaard AG, Due-Rasmussen D, Folke F, Charlot MG, Jepsen RMHG, Wiberg S, Donnino M, Kurth T, Høybye M, Sindberg B, Holmberg MJ, Granfeldt A. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2021 Oct 26;326(16):1586-1594. doi: 10.1001/jama.2021.16628. PMID: 34587236; PMCID: PMC8482303.
Link to Article (NOT FREE)

Haukoos J, Douglas IS, Sasson C. Vasopressin and Steroids as Adjunctive Treatment for In-Hospital Cardiac Arrest. JAMA. 2021 Oct 26;326(16):1583-1585. doi: 10.1001/jama.2021.15460. Erratum in: JAMA. 2021 Nov 9;326(18):1874. PMID: 34587235.
Link to Editorial (NOT FREE)

Holmberg MJ, Granfeldt A, Mentzelopoulos SD, Andersen LW. Vasopressin and glucocorticoids for in-hospital cardiac arrest: A systematic review and meta-analysis of individual participant data. Resuscitation. 2022 Jan 3;171:48-56. doi: 10.1016/j.resuscitation.2021.12.030. Epub ahead of print. PMID: 34990764.
Link to Article
Link to FULL FREE PDF

Saghafi F, Bagheri N, Salehi-Abargouei A, Sahebnasagh A. Efficacy of combination triple therapy with vasopressin, steroid, and epinephrine in cardiac arrest: a systematic review and meta-analysis of randomized-controlled trials. J Intensive Care. 2022 Feb 2;10(1):5. doi: 10.1186/s40560-022-00597-5. PMID: 35109925.
Link to Article
Link to FULL FREE PDF

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