Background: Ketamine, a noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist, is a commonly used dissociative anesthetic in neonatology. We have proposed that ketamine reduces fetal stress responsiveness to stimuli that involve reduced oxygen supply to the fetal brain. Previously, we have shown that ketamine inhibits plasma ACTH levels in late-gestation fetal sheep subjected to brachiocephalic artery occlusion (BCO), an ischemic hypoxia model that might activate some of the same direct and reflex responses as hypoxia. Objectives: We performed the current study to test the hypothesis that ketamine pretreatment will reduce fetal ACTH responses to hypoxic hypoxia (HH). Methods: Fetal sheep were chronically catheterized at least 5 days prior to study. Ketamine (3 mg/kg) was administered intravenously to the fetus 10 min prior to normoxia or a period of hypoxia induced by administration of nitrogen gas to the maternal trachea for 30 min. Results: Hypoxia significantly increased both fetal ACTH and cortisol levels in both the control and ketamine groups (p < 0.0005, interaction effect of time·stimulus in two-way ANOVA), and the ACTH response was blunted by ketamine (p < 0.005). Conclusions: Ketamine reduced fetal ACTH responses to HH, possibly due to antagonism of the NMDA receptors in the fetal brain. Interestingly, in contrast to the responses to BCO, ACTH responses to HH were only partially inhibited, suggesting that multiple neurotransmitter pathways mediate the ACTH response to HH.

Keywords:
Endocrinology, Fetal Sheep, Fetus, Hypoxia, N-Methyl-D-aspartate receptor
1.
Bhutta AT: Ketamine: a controversial drug for neonates. Semin Perinatol 2007;31:303-308.
2.
Sinner B, Graf BM: Ketamine; in Schüttler J, Schwilden H (eds): Modern Anesthetics. New York, Springer, 2008, pp 313-333.
3.
Bauchat JR, Higgins N, Wojciechowski KG, McCarthy RJ, Toledo P, Wong CA: Low-dose ketamine with multimodal postcesarean delivery analgesia: a randomized controlled trial. Int J Obstet Anesth 2011;20:3-9.
4.
Joel S, Joselyn A, Cherian VT, Nandhakumar A, Raju N, Kaliaperumal I: Low-dose ketamine infusion for labor analgesia: a double-blind, randomized, placebo controlled clinical trial. Saudi J Anaesth 2014;8:6-10.
5.
Reich DL, Silvay G: Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989;36:186-197.
6.
Haas DA, Harper DG: Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog 1992;39:61-68.
7.
Orser BA, Pennefather PS, MacDonald JF: Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 1997;86:903-917.
8.
Akinfiresoye L, Tizabi Y: Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology (Berl) 2013;230:291-298.
9.
Himmelseher S, Pfenninger E, Kochs E, Auchter M: S(+)-ketamine up-regulates neuronal regeneration associated proteins following glutamate injury in cultured rat hippocampal neurons. J Neurosurg Anesthesiol 2000;12:84-94.
10.
Powers MJ, Wood CE: Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion. Am J Physiol Regul Integr Comp Physiol 2007;292:R1542-R1549.
11.
Matsumoto LC, Cheung CY, Brace RA: Increased urinary flow without development of polyhydramnios in response to prolonged hypoxia in the ovine fetus. Am J Obstet Gynecol 2001;184:1008-1014.
12.
Betremieux P, Carre P, Pladys P, Roze O, Lefrancois C, Malledant Y: Doppler ultrasound assessment of the effects of ketamine on neonatal cerebral circulation. Dev Pharmacol Ther 1993;20:9-13.
13.
Raff H, Wood CE: Effect of age and blood pressure on the heart rate, vasopressin, and renin response to hypoxia in fetal sheep. Am J Physiol 1992;263:R880-R884.
14.
Bristow J, Rudolph AM, Itskovitz J, Barnes R: Hepatic oxygen and glucose metabolism in the fetal lamb. Response to hypoxia. J Clin Invest 1983;71:1047-1061.
15.
Blanco CE, Dawes GS, Hanson MA, McCooke HB: The response to hypoxia of arterial chemoreceptors in fetal sheep and new-born lambs. J Physiol 1984;351:25-37.
16.
Boekkooi PF, Baan J Jr, Teitel DF, Rudolph AM: Effect of drugs on chemoreceptor responsiveness in fetal sheep. Pediatr Res 1995;38:938-943.
17.
Giussani DA, Spencer JA, Moore PJ, Bennet L, Hanson MA: Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. J Physiol 1993;461:431-449.
18.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Stertz L, Kapczinski F, Gavioli EC, Quevedo J: Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:450-455.
19.
Nistico G, Pisanti N, Rotiroti D, Preziosi P, Cuocolo R, de Martino G, Nistico GM: Effects of althesin and ketamine on resting and stress stimulated adrenocortical activity in rats. Br J Anaesth 1978;50:891-897.
20.
Knutson N, Wood CE: Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis. Am J Physiol Regul Integr Comp Physiol 2010;299:R365-R370.
21.
Tong H, Lakhdir F, Wood CE: Endogenous prostanoids modulate the ACTH and AVP responses to hypotension in late-gestation fetal sheep. Am J Physiol 1998;275:R735-R741.
22.
Wood CE: Sinoaortic denervation attenuates the reflex responses to hypotension in fetal sheep. Am J Physiol 1989;256:R1103-R1110.
23.
Wang J, Rong W, Hou G, Wang W, Yuan W: Evidence that NMDA receptors mediate the responses of putative RVLM presympathetic neurons to vagal afferent stimulation in rats. J Auton Nerv Syst 1998;73:93-100.
24.
Persson J: Wherefore ketamine? Curr Opin Anaesthesiol 2010;23:455-460.
25.
Kohrs R, Durieux ME: Ketamine: teaching an old drug new tricks. Anesth Analg 1998;87:1186-1193.
26.
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994;51:199-214.
27.
Castro MI, Valego NK, Zehnder TJ, Rose JC: The ratio of plasma bioactive to immunoreactive ACTH-like activity increases with gestational age in the fetal lamb. J Dev Physiol 1992;18:193-201.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.