Etomidate Again Linked to Adrenal Suppression

By Nathan Shapiro, MD, MPH, Research Director, Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Emergency Medicine, Boston, MA. Dr. Shapiro is on the speaker’s bureaus of Eli Lilly and Edwards Life Sciences and is a researcher for Biosite.

Source: Malerba G, et al. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med 2005:31:388-392.

Etomidate is a commonly used anesthetic induction agent in the emergency department. Its predictable dosing and favorable hemodynamic profile make it an appropriately popular choice to use as part of a rapid sequence induction cocktail. However, emerging literature also attributes increased mortality risk to adrenal suppression, especially in patients with sepsis. To complete the story, there also are studies that show steroid supplementation in critically ill septic patients with adrenal suppression may reverse these effects and provide a mortality benefit in these patients. This investigation reports on the risk of adrenal suppression in recently intubated patients in intensive care units.

The specific goal of this study was "to study the factors associated with relative adrenocortical deficiency in mechanically ventilated, critically ill patients." This single center, prospective, observational study looked at patients who were likely to need mechanical ventilation for at least 24 hours. Exclusion criteria were prior mechanical ventilation for more than 6 hours, a stay in another intensive care unit, or the need for steroids. Patients underwent a corticotropin stimulation test (i.e., cortisol measurement at baseline and 60 minutes after receiving 250 micrograms of corticotropin) and were considered nonresponders (i.e., adrenal suppression) when the absolute increase in cortisol level was less than 90 micrograms/liter.

The 62 patients in the study had a mean age of 63 years, mixed etiologies of illness (e.g., cardiogenic shock, coma, sepsis), and were fairly ill according to their severity of illness scores. On a univariate basis, the risk factors for adrenal suppression as defined by an inadequate response to a corticotropin stimulation test were male sex, worse severity of illness scores, lower mean arterial blood pressure, lower creatinine clearance, vasopressor agent use, and a single bolus of etomidate. Thus, if the patient was male, more critically ill, or had received etomidate, there was an unadjusted association with adrenal suppression at 24 hours. Finally, on a multivariate analysis, a single bolus of etomidate was an independent risk factor (OR 12.2, 95% CI 3.0 - 50) for adrenal suppression while female gender was protective (OR 0.13, CI 0.03 - 0.57). There was not enough statistical power to comment on mortality risk of etomidate, but 70.4% of nonresponders died compared with 31.4% of responders (p = 0.005).

The authors concluded that a single dose of etomidate in critically ill patients could be a major factor in reduced adrenal function at 24 hours. They cautioned that the implications of these findings call for a larger investigation to look at the effect on outcomes that this adrenal suppression may have. Essentially, they called for a re-appraisal of the risk-benefit ratio for etomidate in the critically ill patient.

Commentary

This is a provocative single center investigation in a relatively limited number of patients from a heterogeneous patient population. The study found an association between etomidate use and failure to respond to a corticotropin stimulation test at 24 hours. That being said, there is ample opportunity for confounding where more critically ill (i.e., hypotensive) patients may have been preferentially given etomidate due to its negligible effects on hemodynamic stability. There also are a number of other opportunities for unmeasured confounding in this nonrandomized study. Finally, there is an association with adrenal suppression, but the effect on mortality was not analyzed.

So, is this study definitive evidence that we should not use etomidate for induction anymore? What about use in septic patients? To keep things in perspective, this is another piece of circumstantial evidence to add to the data in this field. We know that adrenal suppression is associated with worse outcomes, but we do not really know why. We know that septic and other critically ill patients often are adrenally suppressed, but we do not know how. Now, we think that etomidate is associated with short-term adrenal suppression, but we do not know the importance of this fact. We also have to weigh the benefit of rapid airway control using an agent with a stable hemodynamic profile, where there are few other alternatives with this property. We do know of the dangers of poor perfusion and profound hypotension; in some cases this needs to be avoided, even at the risk of short-term adrenal suppression. There are three approaches until more data are available: 1) don’t react too quickly—wait for outcomes-based studies; 2) avoid etomidate and select an alternative agent when safe to do so; and 3) initiate steroid supplementation in patients who likely will be affected by adrenal suppression, followed by corticotropin stimulation testing, and halt steroids after adrenal suppression is resolved. Although perhaps more questions are raised than answered in this study, it is important to be aware of the potential downstream effects of the use of etomidate as an induction agent in emergent airway treatment, and to be cognizant of these effects until we have more definitive studies to guide our choices in the future.