Losing faith in "evidence-based medicine": Etomidate and sepsis

In an era where evidence-based medicine is the goal, it is vitally important for practitioners to understand how to prioritize and interpret the onslaught of data coming at us. 

This fact was driven home for me with a recent publication. Several weeks ago an article was published in Critical Care Medicine entitled "Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis."

The point of this post is not to debate if etomidate should be used to intubate septic patients. Etomidate very well may kill people with sepsis. I just don't know from the data currently available. Using this meta-analysis as an example, the goal is to point out two important areas where we could stand to sharpen our literature evaluation skills.

Point #1: Choose (and interpret) your titles wisely.

It is an overwhelming task to skim through several journals' Table of Contents each month. In a specialty such as Emergency Medicine, many relevant articles appear in non-EM journals making it even more challenging. It's tempting to think we know what an article concluded, based solely on its title.

This point particularly applies to those who publish. But readers also should use extreme caution if only reading titles and abstracts. Given that the last several articles on this topic found that etomidate did not increase mortality when given as an induction agent to septic patients, I was quite surprised to see this bold title declaring etomidate is associated with mortality. We're all so busy that it would be very easy to simply see this title and assume it to be true, without ever reading the article. That is very dangerous medicine, in my opinion. And, this principle extends far beyond this one meta-analysis. 

I've already seen etomidate avoided in a hypotensive, septic patient based on this article. I've also heard colleagues giving a quick summary of the article to students and residents saying this article "confirms what we already knew." What?!? When did we definitively "know" this? I still can't believe a highly regarded journal such as Critical Care Medicine would allow this article to be published with this title.

Point #2: The meta-analysis is not the end-all-be-all of publications.

We've all sat through some sort of literature evaluation class back in school. When the meta-analysis was described to me as a student, I remember thinking how awesome it was. Let me get this straight... people way smarter than me are going to take all of the articles published on a given topic, perform some fancy (way over my head) statistics, and give us an evidence-based conclusion? Sign me up. Coming out of pharmacy school, I pretty much thought meta-analyses were the cream of the crop when it came to the published literature. How wrong I was.

I shouldn't have to go back and analyze each of the articles the authors used, but that is exactly what I did in this case. Here is what I found:

With regard to mortality, 5 trials were included. The 4 smaller ones mostly demonstrated that etomidate did not increase mortality compared to other agents. However, the one larger trial encompassing 499 of the 865 total patients (58%) did show an increase in mortality. It was published by Cuthbertson, et al in Intensive Care Medicine in 2009.

Let's take a closer look at this ICM study. 

It was such a large contributor to the meta-analysis outcome, it seems important to understand what that trial was all about. Despite the authors calling it an a-priori sub study of the CORTICUS trial, it was actually a post-hoc analysis looking at etomidate's association with mortality. You can read the two published commentaries to the Cuthbertson study by Pallin and Andrade, which each highlight several major issues with the data in this trial. 

The bottom line is that the trial by Cuthbertson was highly flawed and really doesn't give us any insight as to etomidate's contribution to mortality. In fact, one of the biggest critiques was that physicians in the CORTICUS trial were instructed to avoid etomidate due to its propensity to suppress cortisol production. So, when physicians did use it, there was likely a reason for it (ie, the patient was hemodynamically unstable and they didn't have many other good induction agent options). Therefore, etomidate was probably given to the sicker patients already more likely to die from the start. 

If you dig even deeper, you'll find that the Cuthbertson group used two logistical regression models. One showed a nonsignificant increase in mortality while the other showed a significant increase. Of course the statistically significant one was reported in the abstract. The bottom line is that if you use bad data to construct a meta-analysis, you'll end up with a bad meta-analysis.

So where does this leave us?

In part, it means we have to remain as skeptical as ever when reading published articles. We already know titles and abstracts don't give the full picture. Taking into account reporting biases, funding sources, and even authors' personal/professional agendas, it seems we can't always rely on the peer-review process to uphold the highest standards of integrity. The best journals out there aren't immune. One reason I love Free Open Access Meducation (FOAMed) is that the peer-review process is instant and no holds barred. If you post something that is inaccurate or controversial on Twitter or a medical education blog, you will get called out on it. The best part is that the ensuing conversations inevitably lead to knowledge sharing and learning. Isn't that what research is supposed to be about after all?

Dr. Joe Lex said it best on Twitter:

I couldn't agree more.



References:

1. Chan CM, et al. Etomidate is associated with mortality and adrenal insufficiency: A meta-analysis. Crit Care Med 2012;40(11):2945-53. [PMID 22971586]
2. Cuthbertson BH, et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med 2009;35(11):1868-76. [PMID 19652948]
3. Pallin DJ, Walls RM. The safety of single-dose etomidate. Intensive Care Med 2010;36(7):1268-70. [PMIS 20405278]
4. Andrade FM. Is etomidate really that bad in septic patients? Intensive Care Med 2010;36(7):1266-70. [PMID 20405279]

Mythbuster: Urgent dialysis following IV contrast?

Have you ever had to promise the radiologist that you would arrange emergent dialysis for your end-stage renal disease (ESRD) patient after receiving IV contrast?

This myth is even perpetuated in the field of nursing. In fact, what prompted this post was overhearing this very topic discussed between a nurse and a new nurse trainee.

Although there is no supportive data, two theoretical risks have been suggested:

1. An oliguric dialysis patient could progress to an anuric state after IV iodinated contrast administration.
2. The osmotic load from IV contrast could result in pulmonary edema and anasarca in a dialysis patient unable to clear the excess volume.

Mythbuster:
Despite the theoretical concerns, there is no need for urgent dialysis after IV contrast administration in an ESRD patient on chronic dialysis.

The patient should be able to wait until their next scheduled dialysis session. In fact, the 2012 American College of Radiology's Manual on Contrast Media states, "Unless an unusually large volume of contrast medium is administered or there is substantial underlying cardiac dysfunction, there is no need for urgent dialysis after intravascular iodinated contrast medium administration."

As an FYI, the average amount of contrast volume infused for a typical CT scan is around 100 mL.

There you have it, although I'm sure you already knew (or at least suspected).

For a nephrologist's perspective, the Renal Fellow Network blog has a great post on this topic as well: http://renalfellow.blogspot.com/2009/08/prophylactic-hemodialysis-for-iv.html

References

• Younathan CM, et al. Dialysis is not indicated immediately after administration of nonionic contrast agents in patients with end-stage renal disease treated by maintenance dialysis. AJR Am J Roentgenol 1994;163(4):969-71. PMID 8092045
• Morcos SK, et al., and members of the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR). Dialysis and Contrast Media. Eur Radiol 2002;12(12):3026-30. PMID 12439587

Trick of the Trade: IV ceftriaxone for gonorrhea

How many times have you given your patient IM ceftriaxone for that presumed gonococcal infection? ... still counting?

Many of us learned (or at least thought we learned) that ceftriaxone has to be administered IM to get the ‘depot’ effect.

Myth busted: There is no depot effect. IV and IM ceftriaxone have very similar pharmacokinetic profiles. Let me prove it to you, straight from the FDA-approved ceftriaxone package insert.

Time after dose administration (hrs) and Average plasma concentration (mcg/mL)

Dose/route	0.5 hr	1 hr	2 hr	4 hr	6 hr	8 hr	12 hr	16 hr	24 hr
0.5 g IV	82	59	48	37	29	23	15	10	5
0.5 g IM	22	33	38	35	30	26	16	unknown	5

• The plasma concentrations are almost identical after IM and IV administration through 24 hours.
• The volume of distribution is the same for both parenteral routes, too. This means that its penetration into the “affected area” is similar.
• For further proof, the CDC Guidelines recommend IV or IM ceftriaxone interchangeably for most gonococcal infections in infants and children.

Trick of the Trade: 
If the patient already has an IV line, give IV ceftriaxone instead of IM .

While most of the time patients with STD (or STI, if you prefer) complaints don’t have an IV line established, occasionally they do. My hospital stocks 1 gm and 2 gm premixed IV bags of ceftriaxone, so we just give 1 gm IV in these rare cases. But 250mg IV should be just fine.

Of course, the other way to avoid the painful injection is to mix the ceftriaxone with lidocaine... or avoid contracting gonorrhea altogether.


References:

Product Information: ROCEPHIN(R) IV, IM injection, ceftriaxone sodium IV, IM injection. Genentech USA, Inc. (per Manufacturer), South San Francisco, CA, 2010.

Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59(RR-12):1-110. [

PMID: 

21160459]. Free MMWR PDF download.

Mythbuster: Pediatric coin ingestion vs aspiration?

Is this coin in the esophagus or the trachea?

The classic teaching for the Boards exam is:

• Esophageal coins appear in the coronal plane, as shown above.
• Tracheal coins appear in the sagittal plane because of the cartilaginous tracheal rings.

Mythbuster: 
A case series of 8 pediatric patients were documented with coins positioned in a sagittal plane were actually in the esophagus! This data was collected over 15 years.

• Age range 3-17 years old
• Location of coin: 7/8 at level of aortic notch and 1/8 at distal esophagus 

The classic teaching likely still holds true most of the time (sagittal coin = tracheal foreign body), but don't rush to immediate judgment. Take a look at the lateral view, and see where the coin is located with respect to the trachea and airway. It may be more posterior, in which case, it's in the esophagus.

Thanks to Dr. Matt Anderson (Resident at Univ. of Wisconsin EM program) for the tip!


Reference

Schlesinger AE, Crowe JE. Sagittal orientation of ingested coins in the esophagus in children. AJR Am J Roentgenol. 2011 Mar;196(3):670-2. Pubmed .