Infectious disease/original research
A Comparison of the Effects of Etomidate and Midazolam on Hospital Length of Stay in Patients With Suspected Sepsis: A Prospective, Randomized Study

Presented as an abstract at the Society of Academic Emergency Medicine Midwest Regional Meeting, September 2009, Ann Arbor, MI; and the American College of Emergency Physicians Scientific Assembly and Research Forum, October 2009, Boston, MA.
https://doi.org/10.1016/j.annemergmed.2010.05.034Get rights and content

Study objective

Etomidate, a widely used induction agent for rapid sequence intubation in the emergency department (ED), causes measurable adrenal suppression after a single bolus dose. The clinical significance of this adrenal suppression in patients with sepsis remains controversial. We seek to determine the difference in hospital length of stay between patients with suspected sepsis who receive either etomidate or midazolam during intubation in our ED.

Methods

We performed a prospective, double-blind, randomized study of patients with suspected sepsis who were intubated in our ED during an 18-month period. Eligible patients who were critically ill and were suspected of having sepsis were randomized to receive either etomidate or midazolam before intubation.

Results

A total of 122 patients were enrolled; 59 received midazolam and 63 received etomidate. Two patients in the etomidate group were lost to follow-up. Patient baseline characteristics were similar between groups. There were no significant differences in median hospital length of stay (9.5 versus 7.3 days), ICU length of stay (4.2 versus 3.1 days), or ventilator days (2.8 versus 2.1) between patients who received midazolam and those who received etomidate, respectively. Inhospital mortality was 21 of 59 (36%; 95% confidence interval 24% to 49%) for patients who received midazolam and 26 of 61 (43%; 95% confidence interval 30% to 56%) for patients who received etomidate. For patients who survived to hospital discharge, the median length of stay was 11.3 days in the midazolam group versus 11.8 days in the etomidate group; for patients who died, the median length of stay was 2.9 days in the midazolam group versus 3.3 days in the etomidate group.

Conclusion

Patients with suspected sepsis and who received a single bolus dose of etomidate for rapid sequence intubation showed no significant increase in hospital length of stay compared with patients who received a single bolus dose of midazolam.

Introduction

Etomidate is widely used as an induction agent before emergency endotracheal intubation primarily because it allows for a rapid, smooth, and hemodynamically stable intubation.1, 2, 3 Concern about the use of etomidate in critically ill patients emerged in the early 1980s, soon after its introduction, when The Lancet published letters to the editor describing increased mortality in trauma patients in the ICU who were continuously sedated with etomidate.4, 5 These patients had a greater than 50% increase in mortality compared with patients receiving no etomidate, despite the similarities in their severity of illness. Concern arose that the increase in mortality might be due to the effect of etomidate on suppression of adrenocortical function, which had been reported in animals and in critically ill patients.6, 7, 8 This observation led to a warning being added to the package insert that cautioned against the use of etomidate as a prolonged infusion, citing the “hazards of prolonged suppression of endogenous cortisol and aldosterone production.” This warning resulted in a cessation in the use of etomidate for continuous sedation.9

Etomidate exerts its effects through reversible and dose-dependent blockade of 11-β-hydroxylase and, to a lesser extent, 17-α-hydroxylase, both of which facilitate the conversion of cholesterol to cortisol. Decreased cortisol and aldosterone levels have been documented in several studies and occur approximately 30 minutes after a single bolus dose of etomidate, with the duration of suppression lasting as long as 24 hours and perhaps even 48 hours.10, 11, 12, 13, 14, 15, 16, 17 Whether this temporary and reversible adrenal suppression is of measurable clinical significance is the subject of extensive and often fervent discussion but has yet to be determined.13, 14, 18, 19, 20, 21, 22, 23, 24

Multiple studies have found associations between single doses of etomidate and adverse outcomes, such as increases in mortality, hospital length of stay, ICU length of stay, and duration of mechanical ventilation.10, 12, 15, 25, 26, 27, 28 In only one of these studies, of trauma patients rather than patients with sepsis, were the patients randomized to receive etomidate12; in the other studies, use of etomidate was at the discretion of the treating physician, thereby limiting the capacity to derive firm conclusions about its effects.

Our goal in this study was to determine the effect of a single dose of etomidate on hospital length of stay by comparing length of stay of patients with suspected sepsis who received midazolam to those who received etomidate during rapid sequence intubation in the emergency department (ED).

Section snippets

Study Design

In this prospective, randomized, double-blind, clinical trial, we compared the hospital length of stay of patients who received etomidate (0.3 mg/kg dose) with the length of stay of patients who received midazolam (0.1 mg/kg dose) intravenously for sedation before rapid sequence intubation. In an earlier prospective observational study in our ED, in which the choice of medication for patients with sepsis requiring emergency intubation was made by the treating physician, of 106 patients during a

Characteristics of Study Subjects

Figure 1 shows the study flow diagram. Throughout the study period, 303 patients were eligible for enrollment, defined as patients who were intubated in the ED and had a presumed infectious cause for illness. Of these, a total of 122 patients were enrolled; 63 received etomidate and 59 received midazolam (intention-to-treat analysis). The primary reason for not enrolling patients was the lack of an available study investigator, study coordinator, or ED pharmacist to facilitate enrollment of the

Limitations

Because of limitations in the availability of study investigators and pharmacists, we were unable to enroll all potentially eligible patients, raising the possibility that our study sample was not representative of our entire patient population. Enrolled patients were nevertheless similar to patients not enrolled. The use of additional adjunctive therapies such as activated protein C, tight glucose control, and low-tidal-volume ventilation may also have varied between groups and was not

Discussion

Etomidate is an ideal agent for use in the patient with sepsis because of its predictability in dosing, reliable hypnotic effect, rapid onset, and short duration of effects and because it has no effect on histamine release, which contributes to its hemodynamic stability.2 However, many previous studies have suggested adverse outcomes from the use of single-bolus etomidate in patients with sepsis, including an absolute increase in mortality ranging from 15% to almost 40%,13, 25, 26 and trends

References (36)

  • P. Jabre et al.

    Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

    Lancet

    (2009)
  • P.J. Zed et al.

    Intubating conditions and hemodynamic effects of etomidate for rapid sequence intubation in the emergency department: an observational cohort study

    Acad Emerg Med

    (2006)
  • P. Preziosi et al.

    Etomidate and corticotrophic axis

    Arch Int Pharmacodyn Ther

    (1982)

  • Etomidate [package insert]

    (2007)
  • M. den Brinker et al.

    One single dose of etomidate negatively influences adrenocortical performance for at least 24h in children with meningococcal sepsis

    Intensive Care Med

    (2008)
  • M. den Brinker et al.

    Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality

    J Clin Endocrinol Metab

    (2005)
  • A.N. Hildreth et al.

    Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study

    J Trauma

    (2008)
  • G. Malerba et al.

    Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation

    Intensive Care Med

    (2005)

    • Cited by (0)

    Supervising editor: Alan E. Jones, MD

    Author contributions: KLT, HFW, RTS, and EBK contributed to the study conception and design. KLT, HFW, RTS, KHR, and EBK contributed to critical revision of the article for important intellectual content. EBK was responsible for study supervision. RTS and KHR were responsible for administrative, technical, and material support. KLT and EBK drafted the article, obtained funding, had full access to all the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. KLT, RTS, KHR, and EBK acquired the data. KLT, HFW, and EBK were responsible for analysis and interpretation of the data and statistical analysis. EBK takes responsibility for the paper as a whole.

    Reprints not available from the authors.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Financial support was provided by an Emergency Medicine Foundation Resident Research Grant.

    Provide feedback on this article at the journal's Web site, www.annemergmed.com.

    Please see page 482 for the Editor's Capsule Summary of this article.

    Publication date: Available online September 15, 2010.

    View full text
    Copyright © 2010 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.