Epi Timing in Cardiac Arrest (Part 2)

In our last post we examined the effect of the chosen resuscitation end-time on the overall duration of the resuscitation and how that affected the calculated mean time-interval between epinephrine doses. It’s worth reviewing quickly before we resume our discussion here.

The major next point in our examination of the Warren et al. paper on epinephrine dosing in cardiac arrest is a look at the endpoints they used to define a “cardiac arrest.” There were two different ways to hit STOP on the clock measuring duration-of-resuscitation: death or return of spontaneous circulation (ROSC) lasting > 20 minutes. Both have issues.

The former is pretty convenient from a charting standpoint, the “time of death,” but it also has the chance to introduce a lot of bias. It’s my personal experience that epi often flows fast-and-furious early in the code. As time drags on and the chance of a good outcome drops, however, the propensity for other interventions increases (“Try a central line with my off-hand? Why not!?”) and group interest in giving more epi decreases. The data certainly seems to reflect that, with Table 1 clearly showing a dramatic increase in arrest duration accompanying the longer dosing-intervals.

Click to enlarge.

Click to enlarge.

That’s a highly-edited excerpt from Table 1; the original table is gigantic with a ton of characteristics listed, but most of them were pretty comparable across all of the dose-intervals. But that, that is something…

One factor at play is a form of selection bias that I guess I could call an anti-length bias (someone out there correct me if there’s a better term for this). Usually length bias is discussed in the setting of cancer screening, where faster growing cancers are less likely to be picked up by screening but more likely to be malignant and fatal. As a result, the patients who survive long enough to be picked up on screening have already self-selected to be a lower-risk for an aggressive tumor and thus have a lower mortality.

Here, by definition, only patients who stayed in arrest at least 9 minutes could ever populate the 9-10 min/dose group. As a result the shorter dosing-interval groups ended up with a disproportionate amount of patients with shorter arrest durations, and correspondingly, lower mortality. Not only do patients do better the sooner they come out of cardiac arrest, but with an average arrest duration of 7.6 min in the 1-3 min/dose group, the great majority of those patients must have been experiencing ROSC. This study only looked at patients experiencing their first in-hospital cardiac arrest, so it’s highly unlikely most of those patients would have been declared dead after only an average of 7.6 min of CPR, leaving ROSC as the only other outcome.

These patients could still go on to experience in-hospital mortality later, but by achieving ROSC they certainly carry a better overall prognosis than patients who died and stayed dead. Disproportionately populating the short-interval group with these ROSCers will skew their mortality lower.

And that isn’t all. Recall that the other stop-point of a defined “cardiac arrest” event was ROSC lasting at least 20 minutes. This is hugely important. At first glance it may seem like a good endpoint because lots of resuscitated patients tend to go back into arrest, especially during the first ten minutes, but it absolutely kills this study (pardon the wording).

The population studied in this paper was comprised only of patients from the intensive care unit and inpatient medical floors. These are not patients who usually experience a sudden cardiac arrest; by definition they had to make it upstairs to have even been considered. Instead, this is a population that tends to spiral downwards over time rather than experience an unexpected catastrophe. The latter still occurs, but at a much lower rate than in the community or even the emergency department.

Anyone who’s been at this for even a modest amount of time has seen the patient with a BP of 50/30 mmHg and a rhythm on the monitor who then “loses pulses.” It’s uncertain whether they actually have a cardiac output but a Code Blue is announced, the patient is given 1mg of epinephrine, and then BOOM, pulses come back.

This hypothetical patient could achieve ROSC with the first dose of epi one minute after the Code was announced, keep a decent cardiac output for the next 10 minutes, and then loses her pulses again. You know this game?

The clock has not reset and this is still considered the same “code” according to this study. As before she responds to a dose of epi and then manages to keep her pulses for at least 20 more minutes following the administration of a norepinephrine drip. The clock is now stopped at the second time she regained pulses. So, in essence, she received one additional dose of epi over approximately 10 minutes and will be evaluated in the 9-10 min dosing group, plus her duration of “cardiac arrest” is now recorded at something like 12 min instead of 2 min. Never mind that categorization doesn’t even come close to capturing what really happened, but that’s how she’ll be analyzed in this study.

To the author’s credit they did exclude patients with intervals > 10 min for this reason, but that eliminates only the most blatant of cases; plenty will still end up in the data. They also excluded patients who received a non-epinephrine vasopressor during the arrest, but this doesn’t account for all of the patients described by the scenario above who received one after “final” ROSC to stave off further arrest.

So, what we see at this point is that this paper is a horrible mess of cross-pollination between study categories. Short dosing-interval patients are being placed into longer-interval categories because of the resuscitation-length issues covered Part 1 and intermittent-ROSC factors just discussed. On the other hand, the patients who still managing to make it into the short dosing-intervals are going to show markedly decreased mortality compared to the longer dosing-intervals because many of the latter needed to “stay dead longer” in order to even make it into their dosing-group.

How will this all pan out? Stay tuned for Part 3 where will will finally discuss the outcome data…

Epi Timing in Cardiac Arrest (Part 1)

There’s a new study by Warren et al. out in the most resent issue of Resuscitation that examines the use of epinephrine during in-hospital cardiac arrest. It also purports to show a possible benefit to non-standard dosing regimens.

Your pupils just dilated slightly… I’ve been watching the new season of Sherlock.

Click image for source.

Epinephrine is a touchy subject in the world of critical care, both prehospital and in-hospital, so this study is bound to garner a bit of attention. The big questions are whether that attention is deserved and what to do with the information that’s contained within.

If you want to cut to the skinny, it looks like this data isn’t nearly strong enough to affect the next round of ACLS/ILCOR guidelines… at least I hope it won’t. It’s not just weak data; it’s fundamentally flawed and probably garbage. If you care why, and I think you should, allons-y!

Click image for source.

…there’s also been some Doctor Who thrown in.

From the abstract, the aim of the paper was, “to evaluate the association between epinephrine average dosing period and survival to hospital discharge in adults with an in-hospital cardiac arrest.” The data examined was prospectively gathered and retrospectively examined from approximately 21,000 in-hospital cardiac arrests at about 500 hospitals in the Get With The Guidelines – Resuscitation (GWTG-R) registry.

This means that the data was gathered with the knowledge that it would be used in future research, but at the time of entry that exact use was unknown. At a later data the authors then looked backwards at a near ten-year chunk of the data and attempted to parse out how varying dose-intervals of epinephrine were associated with patient outcomes. It’s a noble pursuit and an important subject that has been understudied in the past, but one of the reasons why it’s not often researched is that it is difficult to examine outside of the setting of a randomized controlled trial. This design can make for decent hypothesis-generation in the right scenario, but here it’s pretty weak-sauce.

It’s a pretty big registry, and that can be a good thing if you’re asking simple questions with simple answers. The problem is that we’re not asking a simple question. It’s notoriously difficult to record the timing of medications during a cardiac arrest, and in-fact, the GWTG-R registry doesn’t even record epinephrine timing after the first dose. How could the researchers even attempt this study?

Click image for source.

Well, the GWTG-R registry does record the total number of doses of epinephrine administered during the arrest, along with the time to return of spontaneous circulation (ROSC). The authors, looking at resuscitations that received more than one dose of epi, then divided the time from the first dose of epinephrine to the end of the resuscitation by the subsequent number of doses to come up the average amount of time between doses. Here’s an example of an ideal patient receiving epi every 5 minutes.

5-6min Epi Interval

q5min dosing categorized as “5 to <6 min dosing”

If you’ve ever been involved in a resuscitation you will quickly realize that this way of calculating epinephrine timing in no way reflects real-world practice. Resuscitations are messy affairs and dose-timing can be all over the place during a single arrest, with one interval of 2 min, another of 8 min, and another of 2 min. While that may average out to a rate of one dose every four minutes, it’s probably very different from giving the patient evenly spaced q4min doses of epi.

The authors recognized that this is only an estimate of the dosing intervals, but another issue that compounds this mess with the timing is that is exceptionally dependent on when ROSC was noted and recorded. The same “q5min” dosing pattern shown above can result in at least four different interval-stratifications depending on the length of resuscitation and the time ROSC is recognized.

6-7min Epi Interval

q5min dosing categorized as “6 to <7 min dosing”

7-8min Epi Interval

q5min dosing categorized as “7 to <8 min dosing”

9-10min Epi Interval

q5min dosing categorized as “9 to <10 min dosing”

You’ll also note that all of the above patterns bias towards estimating a longer interval than what was really prescribed and administered, never shorter. This will come up later.

To keep things reasonable let’s end our initial discussion there for today, but if you like this stuff look forward to Part 2 (and 3… and maybe 4) being posted over the coming days.



Hopefully you’re out there reading the research and trying to figure out what you should be doing and why. But inevitably, when you get to the results, they’re reported using a baffling array of acronymic metrics. Some are fairly intuitive; some are truly confusing; but you should understand them all. Here’s a quick run-through on the most common terms, particularly odds ratios, absolute risk reduction, relative risk, and NNT, using two recently-added studies (Kudenchuk 1999 and Jacobs 2011) as examples.