Zhao, Lisa MD; Lovato, Luis M. MD
Etomidate is the most widely used induction agent in emergency medicine. For rapid sequence intubation (RSI), it has many “ideal” characteristics, including rapid onset, short duration, superior reliability, and a minimal effect on blood pressure. Its hemodynamic profile might seem particularly useful in septic patients who have tenuous blood pressures that are often difficult to maintain without supportive measures.
Unfortunately, as is always the case in medicine, no drug is perfect. Etomidate has long been scrutinized for its potential to cause adrenal suppression. In 1984, a retrospective review by Watt and Ledingham reported a 49 percent spike in mortality rate (28% to 77%) in multiple-trauma ICU patients sedated with continuous infusions of etomidate. (Anaesthesia 1984;39:973.) Mortality rates fell back to normal levels when etomidate was discontinued as a maintenance anesthetic.
It is clear from several studies that even single-dose etomidate leads to a depression of corticosteroid synthesis by reversibly inhibiting 11-b-hydroxylase, an important enzyme in the complex pathway of steroidogenesis. Fortunately, this effect appears transient. In a 2001 prospective, randomized, controlled trial comparing single-dose induction using midazolam vs. etomidate, Schenarts et al measured adrenocortical function at four, 12, and 24 hours post-intubation. (Acad Emerg Med 2001;8:1.) At four hours, 30 percent of etomidate patients had abnormal cosyntropin stimulation tests (CSTs), but by 12 hours, almost all etomidate patients had normal CSTs with no significant difference between the groups.
Let's assume this very reasonable premise is true. Etomidate does indeed have a transient effect on steroid synthesis, but there is a much more important question the emergency physician really needs answered before giving up on this otherwise ideal induction agent. Is this transient adrenal suppression from single-dose etomidate clinically relevant?
To date, no studies have been sufficiently powered to show differences in mortality or important secondary outcomes. The Schenarts study comparing midazolam and etomidate induction observed no difference in length of intubation, ICU stay, or hospitalization. Only 31 patients were enrolled in that trial, however, with 13 of them excluded for various reasons from the final analysis. Another trial in 2008 by Hildreth et al resulted in a completely contradictory clinical conclusion. Adult trauma patients randomized to receive RSI induction with either fentanyl/midazolam or etomidate showed that the etomidate group had greater adrenal suppression, more ventilator days, longer ICU stays, and longer hospital stays. (J Trauma 2008;65:573.) But again, this study was very small, enrolling a total of only 30 patients, making it difficult to make meaningful conclusions about the effect of etomidate on these important clinical outcomes.
A Comparison of the Effects of Etomidate and Midazolam on Hospital Length of Stay in Patients with Suspected Sepsis: A Prospective, Randomized Study
Tekwani KL, et al
Ann Emerg Med
Tekwani et al reports on a relatively larger, prospective, randomized control trial of etomidate (0.3mg/kg) versus midazolam (0.1 mg/kg) used for rapid sequence intubation of patients meeting sepsis criteria. Mean hospital length of stay was the primary endpoint. Of the 122 patients enrolled, there was no significant difference in the mean hospital stay (midazolam 9.5 days, etomidate 7.3 days). There also were no significant differences in secondary outcomes between those who received midazolam vs. etomidate: ventilator days (2.8 days vs. 2.1 days), ICU stay (4.2 days vs. 3.1 days), or in-hospital mortality (36% vs. 43%).
To date, this is the only double-blinded, randomized controlled trial of septic patients designed specifically to look at the effect of single-dose etomidate induction on hospital stay and patient outcomes. These results certainly add legitimacy to the pro etomidate argument. But, unfortunately, the overall body of literature on this topic is not only sparse but also conflicting, making it difficult to put this controversy to rest.
What about induction alternatives? Midazolam was considered the control induction agent for many of the studies looking at etomidate, but in comparison, benzodiazepines are less reliable, and have a much longer duration of action, both less than ideal characteristics for an RSI agent. Interestingly, there also are some reports that implicate benzodiazepines as blunting the function of the adrenal cortex (aldosterone, cortisol) and the adrenal medulla (epinephrine). (Horm Metab Res 1998;30[6-7]:464; Psychopharmacology (Berl) 1996;128:21.) If you think about it, would it really be surprising to find that a sedative blunts the fight-or-flight acute stress response?
Propofol, another commonly used agent for RSI, has the advantage of being extremely short-acting, but is also prone to cause hypotension, making it a poor choice for the septic patient. Ketamine is perhaps the most promising alternative induction agent in patients sensitive to hypotension. Ketamine not only has a favorable pharmacodynamic profile as an induction agent (i.e., rapid onset, short-acting, multiple effects), but rather fortuitously also stimulates the cardiovascular system. Jabre et al recently studied etomidate versus ketamine for RSI, and reported no significant differences in hospital–oriented outcomes or mortality. (Lancet 2009;374:293.)
In the end, what exactly is the take-home point for the front-line emergency physician? Presently, there seems to be insufficient evidence to warrant a change in the way we choose to induce. We know single-dose etomidate causes transient adrenal suppression, but the clinical relevance of this is questionable. Etomidate also has many pharmacodynamic benefits and advantages over alternative induction agents. For now, old, faithful etomidate is probably not in danger of being dethroned as the leading induction agent for emergent RSI.
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Dr. Zhao is a senior...Image Tools
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