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.
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…