Etomidate: Evaluating adrenal suppression and increased mortality

Introduction
-Etomidate is an intravenous nonbarbiturate hypnotic
-Developed in the 1970s, found to be an effective hypnotic [1]
-Used as anesthesia induction agent and for first decade, used as sedative infusion
-Discovered to cause adrenal suppression and increased mortality in some critically ill patients
-Now predominately used as sedative medication in rapid sequence intubation (RSI)

​Structure

- Available as 2mg/mL solution in 35% propylene glycol solution
- Available in lipid solution in Europe, reportedly less pain on infusion
- Sedative bolus at 0.2-0.4mg/kg, general anesthesia with continuous infusion of 30-100ug/kg/min

Pharmacology/Pharmacokinetics [1]
- pKa of 4.2 and is hydrophobic at physiologic pH
- Formulated in 35% propylene glycol to increase solubility
- 75% protein bound with large volume of distribution 74.9 L/kg due to high fat solubility
- Three compartment model of pharmacokinetics for single bolus of etomidate
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​Compartment 1: rapid distribution into highly perfused tissue
Compartment 2: redistribution into peripheral tissues (muscles)
Compartment 3: terminal metabolism

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- Onset of action in <1min, duration is approximately 5 min
- Metabolism dependent on hepatic esterase activity, which hydrolyzes to carboxylic acid and an ethanol leaving group
- Carboxylate metabolite mostly excreted in urine
- Metabolic t1/2 ranges from 2-5 hours
- Elderly or ill patients require lower etomidate doses due to reduced protein binding and reduced clearance

​Mechanism of Action:
- Non barbiturate hypnotic active at the GABAA receptor, specifically the β2 and β3
- Etomidate positively modulates GABAA activation by agonists
- Slow postsynaptic current decay, prolonging postsynaptic inhibition
- Blocks 11β-hydroxylase in the steroidogenesis pathway [2]
- Nitrogen atom of the imidazole ring interacts with the active binding site of the enzyme

Toxicity
- Propylene glycol diluent is implicated in development of hyperosmolar metabolic acidosis when used in prolonged infusions
- Cardiovascular side effects include hypotension and tachycardia, less significant than most other sedative agents
- Both proconvulsant and anticonvulsant properties
- Myoclonus- may be caused by etomidate interaction with glycine receptor at the spinal cord level
- Adrenocortical suppression- etomidate blocks of 11β-hydroxylase leading to depressed adrenal production of cortisol and aldosterone

• This has been found in both single dose administrations of etomidate[3] and in prolonged infusions of etomidate[1]
• Adrenal suppression lasting >24hrs following infusion, 6-8hrs following bolus
• Increased mortality
  • Related to prolonged etomidate infusions
  • 1983 study reported retrospective data that showed increased mortality among ICU patients receving prolonged etomidate infusions compared to those receiving benzodiazepine infusions (69% vs. 25%) [4]
• Several studies have cited increased mortality in critically ill patients following a single induction dose of etomidate, however several recent studies refute these conclusions:
  • Etomidate vs. ketamine for RSI in acutely ill patients (KETASED) trial, Lancet 2009
  • Study of 655 patients requiring emergent RSI in prehospital, ED, or ICU
  • No statistically significant difference was seen in sepsis-related organ failure, mortality rates, or intubating conditions between the 2 groups. However, there was a higher incidence of adrenal insufficiency in the etomidate group (defined as serum cortisol <10ug/dL or difference of <9ug/dL sixty min after ACTH stimulation test) – 86% in those with etomidate vs. 56% in those without etomidate use (p<0.0001) [5]
  • Most recent Cochrane systematic review of evidence suggests that “no strong evidence exists that etomidate increases mortality in critically ill patients when compared to other bolus dose induction agents” [6]

Clinical Presentation
- Pain on infusion
- Myoclonus
- Postoperative nausea and vomiting (40%)- few studies have compared etomidate vs. other induction agents. One study has shown this to be comparable to barbituates and higher than propofol [1]
- Adrenocortical inhibition- can manifest as hypotension refractory to fluids and vasopressors

Management
- Pain on infusion- consider pretreatment with 3mL 1% lidocaine
- Nausea and vomiting- symptomatic treatment
- Myoclonus- opioid (fentanyl derivatives, dezocine) [7] , magnesium [8] , ketamine [9] pretreatment
- Adrenal suppression- should we treat with corticosteroids?

• Corticosteroid Therapy of Septic Shock (CORTICUS) trial, NEJM 200810
• Study of 499 critically ill patients in 52 ICUs, 9 countries
• Hydrocortisone shown to hasten recovery of blood pressure in septic shock but did not have an impact on mortality
• Data revealed increased rate of death at 28 days among patients who received etomidate before randomization (40-45.1% in placebo/hydrocortisone groups respectively) vs. those who had not received etomidate before randomization (29.6-31.5% in placebo/hydrocortisone groups respectively; P= 0.03)
• The data in this study were not evaluated in the Cochrane review due to observational nature of etomidate exposure and there was no causation determined. The more recent KETASED trial has suggested no change in mortality data.
• 2012 Surviving sepsis guidelines- Recommend against using corticosteroids if hypotension is responsive to fluids and vasopressors (level 2C). When significant hemodynamic instability remains following fluids and vasopressors, corticosteroids are recommend at an IV dose of 200 mg hydrocortisone every 24 hours [11]

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Future Directions
Novel etomidate agents-
​Carboetomidate- contains pyrrole instead of imidazole, making binding 11β-hydroxylase less effective and thus reducing adrenal suppression [12]
MOC-etomidate- Alteration made to ester moiety that is then rapidly metabolized, producing less profound and shorter-lasting adrenal suppression [12]

​Use in severe Cushing’s syndrome- several case studies outlining the use of etomidate infusions as low as 2.5mg/hr resulting in clinical improvement in hypercortisolism without causing sedative effects [13]

References
1. Forman, S. Clinical and Molecular Pharmacology of Etomidate. Anesthesiology 2011; 114(3): 695-707.
2. de Jong FH, Mallios C, Jansen C, Scheck PA, Lamberts SW. Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab 1984; 59: 1143–47.
3. Hildreth AN, Mejia VA, Maxwell RA, Smith PW, Dart BW, Barker DE. Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study. J Trauma 2008; 65: 573–79.
4. Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983; 321: 1270.
5. P. Jabre, X. Combes, F. Lapostolle, M. Dhaouadi, A. Ricard-Hibon, B. Vivien, Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial, Lancet, Vol. 374, 2009, 293-300
6. Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C. Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database of Systematic Reviews 2015, Issue 1
7.  Li, Z., He, L., Diny, Y., Chen, H. Dezocine pretreatment prevents myoclonus induced by etomidate: a randomized, double-blinded controlled trial, Anesthesiology 2015. 29(1):143-145. 
8. Yelken, B., Un, B., Ceyhand, D. Prevention of etomidate-related myoclonus in anesthetic induction by pretreatment with magnesium. J. Res Med Sci 2011, 16(11):1490-1494.  
9. Zhou, H., Wu, GN, Xu, HJ, Wu X. Low-dose Ketamine Pretreatment Reduces the Incidence and Severity of Myoclonus Induced by Etomidate: A randomized, Double-Blinded, Controlled Clinical Trial. Medicine 2016, 95(6)
10. Briegel, J. and CORTICUS study group. Hydrocortisone Therapy for Patients with Septic Shock. New Eng J Med 2008. 358(2): 111-124.
11. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med. 2013;41:580–637
12. Sney, J. Novel Etomidate Derivatives. Current Pharm Design 2012, 18: 6253-6256.
13. Price-Newell, J., Daniel, E. Therapy of Endocrine Disease: Steroidogenesis enzyme inhibitors in Cushing’s Syndrome. Eur J Endocrinol 2015. 172: 263-280.

Other sources used include Goldfrank’s 10th edition, Haddad’s 3rd edition, and The Poison Review (www.thepoisonreview.com)
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Authored by: Dr. Cate Lounsbury, MD