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Published in: Intensive Care Medicine 7/2012

01-07-2012 | Experimental

Isoflurane/nitrous oxide anesthesia and stress-induced procedures enhance neuroapoptosis in intrauterine growth-restricted piglets

Authors: Harald Schubert, Michael Eiselt, Bernd Walter, Harald Fritz, Michael Brodhun, Reinhard Bauer

Published in: Intensive Care Medicine | Issue 7/2012

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Abstract

Purpose

There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity.

Methods

This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen.

Results

IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition (P < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets.

Conclusions

There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction.
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Literature
1.
go back to reference Anand KJ, Sippell WG, Aynsley-Green A (1987) Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1:62–66PubMedCrossRef Anand KJ, Sippell WG, Aynsley-Green A (1987) Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1:62–66PubMedCrossRef
2.
go back to reference Weber F (2010) Evidence for the need for anaesthesia in the neonate. Best Pract Res Clin Anaesthesiol 24:475–484PubMedCrossRef Weber F (2010) Evidence for the need for anaesthesia in the neonate. Best Pract Res Clin Anaesthesiol 24:475–484PubMedCrossRef
3.
go back to reference Istaphanous GK, Ward CG, Loepke AW (2010) The impact of the perioperative period on neurocognitive development, with a focus on pharmacological concerns. Best Pract Res Clin Anaesthesiol 24:433–449PubMedCrossRef Istaphanous GK, Ward CG, Loepke AW (2010) The impact of the perioperative period on neurocognitive development, with a focus on pharmacological concerns. Best Pract Res Clin Anaesthesiol 24:433–449PubMedCrossRef
4.
go back to reference Wang C, Slikker W Jr (2008) Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system. Anesth Analg 106:1643–1658PubMedCrossRef Wang C, Slikker W Jr (2008) Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system. Anesth Analg 106:1643–1658PubMedCrossRef
5.
go back to reference Sankaran S, Kyle PM (2009) Aetiology and pathogenesis of IUGR. Best Pract Res Clin Obstet Gynaecol 23:765–777PubMedCrossRef Sankaran S, Kyle PM (2009) Aetiology and pathogenesis of IUGR. Best Pract Res Clin Obstet Gynaecol 23:765–777PubMedCrossRef
6.
go back to reference Bauer R, Walter B, Brust P, Fuchtner F, Zwiener U (2003) Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets. Eur J Obstet Gynecol Reprod Biol 110(Suppl 1):S40–S49PubMedCrossRef Bauer R, Walter B, Brust P, Fuchtner F, Zwiener U (2003) Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets. Eur J Obstet Gynecol Reprod Biol 110(Suppl 1):S40–S49PubMedCrossRef
7.
go back to reference Wollmann HA (1998) Intrauterine growth restriction: definition and etiology. Horm Res 49:1–6CrossRef Wollmann HA (1998) Intrauterine growth restriction: definition and etiology. Horm Res 49:1–6CrossRef
8.
go back to reference Campbell S, Thoms A (1977) Ultrasound measurement of the fetal head to abdomen circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol 84:165–174PubMedCrossRef Campbell S, Thoms A (1977) Ultrasound measurement of the fetal head to abdomen circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol 84:165–174PubMedCrossRef
9.
go back to reference Cox P, Marton T (2009) Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 23:751–764PubMedCrossRef Cox P, Marton T (2009) Pathological assessment of intrauterine growth restriction. Best Pract Res Clin Obstet Gynaecol 23:751–764PubMedCrossRef
10.
go back to reference Jacobsson B, Ahlin K, Francis A, Hagberg G, Hagberg H, Gardosi J (2008) Cerebral palsy and restricted growth status at birth: population-based case–control study. BJOG 115:1250–1255PubMedCrossRef Jacobsson B, Ahlin K, Francis A, Hagberg G, Hagberg H, Gardosi J (2008) Cerebral palsy and restricted growth status at birth: population-based case–control study. BJOG 115:1250–1255PubMedCrossRef
11.
go back to reference Spassov L, Curzi-Dascalova L, Clairambault J, Kauffmann F, Eiselt M, Medigue C, Peirano P (1994) Heart rate and heart rate variability during sleep in small-for-gestational age newborns. Pediatr Res 35:500–505PubMedCrossRef Spassov L, Curzi-Dascalova L, Clairambault J, Kauffmann F, Eiselt M, Medigue C, Peirano P (1994) Heart rate and heart rate variability during sleep in small-for-gestational age newborns. Pediatr Res 35:500–505PubMedCrossRef
12.
go back to reference Walker DM, Marlow N (2008) Neurocognitive outcome following fetal growth restriction. Arch Dis Child Fetal Neonatal Ed 93:F322–F325PubMedCrossRef Walker DM, Marlow N (2008) Neurocognitive outcome following fetal growth restriction. Arch Dis Child Fetal Neonatal Ed 93:F322–F325PubMedCrossRef
13.
go back to reference Chase HP, Welch NN, Dabiere CS, Vasan NS, Butterfield LJ (1972) Alterations in human brain biochemistry following intrauterine growth retardation. Pediatrics 50:403–411PubMed Chase HP, Welch NN, Dabiere CS, Vasan NS, Butterfield LJ (1972) Alterations in human brain biochemistry following intrauterine growth retardation. Pediatrics 50:403–411PubMed
14.
go back to reference Duncan KR, Issa B, Moore R, Baker PN, Johnson IR, Gowland PA (2005) A comparison of fetal organ measurements by echo-planar magnetic resonance imaging and ultrasound. Bjog 112:43–49PubMedCrossRef Duncan KR, Issa B, Moore R, Baker PN, Johnson IR, Gowland PA (2005) A comparison of fetal organ measurements by echo-planar magnetic resonance imaging and ultrasound. Bjog 112:43–49PubMedCrossRef
15.
go back to reference Burke C, Gobe G (2005) Pontosubicular apoptosis (“necrosis”) in human neonates with intrauterine growth retardation and placental infarction. Virchows Arch 446:640–645PubMedCrossRef Burke C, Gobe G (2005) Pontosubicular apoptosis (“necrosis”) in human neonates with intrauterine growth retardation and placental infarction. Virchows Arch 446:640–645PubMedCrossRef
16.
go back to reference Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney JW (2010) Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 112:834–841PubMedCrossRef Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney JW (2010) Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 112:834–841PubMedCrossRef
17.
go back to reference Jevtovic-Todorovic V, Beals J, Benshoff N, Olney JW (2003) Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Neuroscience 122:609–616PubMedCrossRef Jevtovic-Todorovic V, Beals J, Benshoff N, Olney JW (2003) Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain. Neuroscience 122:609–616PubMedCrossRef
18.
go back to reference Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104PubMedCrossRef Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104PubMedCrossRef
19.
go back to reference Rizzi S, Ori C, Jevtovic-Todorovic V (2010) Timing versus duration: determinants of anesthesia-induced developmental apoptosis in the young mammalian brain. Ann N Y Acad Sci 1199:43–51PubMedCrossRef Rizzi S, Ori C, Jevtovic-Todorovic V (2010) Timing versus duration: determinants of anesthesia-induced developmental apoptosis in the young mammalian brain. Ann N Y Acad Sci 1199:43–51PubMedCrossRef
20.
go back to reference Arnold JH, Truog RD, Rice SA (1993) Prolonged administration of isoflurane to pediatric patients during mechanical ventilation. Anesth Analg 76:520–526PubMedCrossRef Arnold JH, Truog RD, Rice SA (1993) Prolonged administration of isoflurane to pediatric patients during mechanical ventilation. Anesth Analg 76:520–526PubMedCrossRef
21.
go back to reference Kinouchi K (2004) Anaesthetic considerations for the management of very low and extremely low birth weight infants. Best Pract Res Clin Anaesthesiol 18:273–290PubMedCrossRef Kinouchi K (2004) Anaesthetic considerations for the management of very low and extremely low birth weight infants. Best Pract Res Clin Anaesthesiol 18:273–290PubMedCrossRef
22.
go back to reference Lerman J, Johr M (2009) Inhalational anesthesia vs total intravenous anesthesia (TIVA) for pediatric anesthesia. Paediatr Anaesth 19:521–534PubMedCrossRef Lerman J, Johr M (2009) Inhalational anesthesia vs total intravenous anesthesia (TIVA) for pediatric anesthesia. Paediatr Anaesth 19:521–534PubMedCrossRef
23.
go back to reference Bauer R, Walter B, Hoppe A, Gaser E, Lampe V, Kauf E, Zwiener U (1998) Body weight distribution and organ size in newborn swine (sus scrofa domestica)—a study describing an animal model for asymmetrical intrauterine growth retardation. Exp Toxicol Pathol 50:59–65PubMedCrossRef Bauer R, Walter B, Hoppe A, Gaser E, Lampe V, Kauf E, Zwiener U (1998) Body weight distribution and organ size in newborn swine (sus scrofa domestica)—a study describing an animal model for asymmetrical intrauterine growth retardation. Exp Toxicol Pathol 50:59–65PubMedCrossRef
24.
go back to reference DeRoth L, Downie HG (1978) Basic cardiovascular parameters in the underweight neonatal swine. Biol Neonate 34:155–160PubMedCrossRef DeRoth L, Downie HG (1978) Basic cardiovascular parameters in the underweight neonatal swine. Biol Neonate 34:155–160PubMedCrossRef
25.
go back to reference Satas S, Haaland K, Thoresen M, Steen PA (1996) MAC for halothane and isoflurane during normothermia and hypothermia in the newborn piglet. Acta Anaesthesiol Scand 40:452–456PubMedCrossRef Satas S, Haaland K, Thoresen M, Steen PA (1996) MAC for halothane and isoflurane during normothermia and hypothermia in the newborn piglet. Acta Anaesthesiol Scand 40:452–456PubMedCrossRef
26.
go back to reference Anand KJ, Soriano SG (2004) Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 101:527–530PubMedCrossRef Anand KJ, Soriano SG (2004) Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 101:527–530PubMedCrossRef
27.
go back to reference Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74PubMedCrossRef Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74PubMedCrossRef
28.
go back to reference Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882PubMed Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882PubMed
29.
30.
go back to reference Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO (2011) Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128:e1053–e1061PubMedCrossRef Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR, Warner DO (2011) Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128:e1053–e1061PubMedCrossRef
31.
go back to reference DiMaggio C, Sun LS, Li G (2011) Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 113:1143–1151PubMedCrossRef DiMaggio C, Sun LS, Li G (2011) Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 113:1143–1151PubMedCrossRef
Metadata
Title
Isoflurane/nitrous oxide anesthesia and stress-induced procedures enhance neuroapoptosis in intrauterine growth-restricted piglets
Authors
Harald Schubert
Michael Eiselt
Bernd Walter
Harald Fritz
Michael Brodhun
Reinhard Bauer
Publication date
01-07-2012
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 7/2012
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-012-2576-2

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