Critical Care Medicine  |   August 2017
Ketamine and Etomidate Down-regulate the Hypothalamic–Pituitary–Adrenal Axis in an Endotoxemic Mouse Model
Author Notes
  • From the Department of Anesthesia and Critical Care (E.B., T.C., J.S., A.L.-S., B.D., V.C.) and the Medical Critical Care Unit (F.T.), Normandy University, UNIROUEN (Rouen University), Rouen University Hospital, Rouen, France; Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Normandy University, UNIROUEN, INSERM (Institut National de la Santé Et de la Recherche Médicale) U982, Rouen, France (E.B., T.C., M.-C.T., A.L.-S., F.M., H.C., V.C.); Institute for Research and Innovation in Biomedicine, Rouen, France (E.B., T.C., M.-C.T., J.S., A.L.-S., F.M., F.T., H.C., V.C.); and the Department of Pharmacology, Normandy University, UNIROUEN, INSERM U1096, Rouen, France (J.S., F.T.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • H.C. and V.C. should be considered equal last authors of this article.
    H.C. and V.C. should be considered equal last authors of this article.×
  • Submitted for publication September 2, 2016. Accepted for publication April 24, 2017.
    Submitted for publication September 2, 2016. Accepted for publication April 24, 2017.×
  • Address correspondence to Dr. Besnier: Normandy University, UNIROUEN, Department of Anesthesia and Critical Care, Rouen University Hospital, 1 Rue de Germont, 76000 Rouen, France. emmanuel.besnier@chu-rouen.fr. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Endocrine and Metabolic Systems / Infectious Disease / Pharmacology
Critical Care Medicine   |   August 2017
Ketamine and Etomidate Down-regulate the Hypothalamic–Pituitary–Adrenal Axis in an Endotoxemic Mouse Model
Anesthesiology 8 2017, Vol.127, 347-354. doi:10.1097/ALN.0000000000001704
Anesthesiology 8 2017, Vol.127, 347-354. doi:10.1097/ALN.0000000000001704
Abstract

Background: We compared the effects of etomidate and ketamine on the hypothalamic–pituitary–adrenal axis during sepsis.

Methods: Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD).

Results: At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11β-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11β-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels.

Conclusions: Our endotoxemic model induces an initial activation of the hypothalamic–pituitary–adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.