Abstract

Background: Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach.

Methods: Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 ug kg^-1 h^-1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure.

Results: Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%.

Conclusions: A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.

Keywords
apoptosis; brain injury; dexmedetomidine; neuroprotection; neurotoxicity; sevoflurane; volatile anaesthetics

*Abstract and full text online at https://bjanaesthesia.org/article/S0007-0912(21)00091-X/fulltext

References

1. • Lin E.P., Lee J.R., Lee C.S., Deng M., Loepke A.W.
   Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies. Neurotoxicol Teratol. 2017; 60: 117-128. PubMed
   • Jevtovic-Todorovic V., Olney J.W.
2. PRO: anesthesia-induced developmental neuroapoptosis: status of the evidence. Anesth Analg. 2008; 106: 1659-1663. PubMed
   • Loepke A.W.
   • McGowan Jr., F.X.
   • Soriano S.G.
3. CON: the toxic effects of anesthetics in the developing brain: the clinical perspective. Anesth Analg. 2008; 106: 1664-1669. PubMed

   US Food & Drug Administration

4. FDA drug safety communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children. 2017 (Available from:) https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs. Date accessed: March , 2021
   • Satomoto M.
   • Satoh Y.
   • Terui K.
   • et al.
5. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 2009; 110: 628-637

   PubMed

   • Lu Y.
   • Wu X.
   • Dong Y.
   • Xu Z.
   • Zhang Y.
   • Xie Z.
6. Anesthetic sevoflurane causes neurotoxicity differently in neonatal naive and Alzheimer disease transgenic mice. Anesthesiology. 2010; 112: 1404-1416

   PubMed

   • Briner A.
   • De Roo M.
   • Dayer A.
   • Muller D.
   • Habre W.
   • Vutskits L.
7. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology. 2010; 112: 546-556

   PubMed

   • Istaphanous G.K.
   • Howard J.
   • Nan X.
   • et al.
8. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 2011; 114: 578-587

   PubMed

   • Kodama M.
   • Satoh Y.
   • Otsubo Y.
   • et al.
9. Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology. 2011; 115: 979-991

   PubMed

   • Ramage T.M.
   • Chang F.L.
   • Shih J.
   • et al.
10. Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats. Br J Anaesth. 2013; 110: i39-46

    PubMedAbstractFull TextFull Text PDF

    • Raper J.
    • Alvarado M.C.
    • Murphy K.L.
    • Baxter M.G.
11. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthesiology. 2015; 123: 1084-1092

    PubMed

    • Lee J.R.
    • Loepke A.W.
12. Does pediatric anesthesia cause brain damage? – addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data. Korean J Anesthesiol. 2018; 71: 255-273

    Google Scholar

    • Davidson A.J.
    • Disma N.
    • de Graaff J.C.
    • et al.
13. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016; 387: 239-250

    PubMedAbstractFull TextFull Text PDF

    • McCann M.E.
    • de Graaff J.C.
    • Dorris L.
    • et al.
14. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019; 393: 664-677

    PubMedAbstractFull TextFull Text PDF

    • Sun L.S.
    • Li G.
    • Miller T.L.
    • et al.
15. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016; 315: 2312-2320

    PubMed

    • Warner D.O.
    • Zaccariello M.J.
    • Katusic S.K.
    • et al.
16. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: the Mayo Anesthesia Safety in Kids (MASK) study. Anesthesiology. 2018; 129: 89-105

    PubMed

    • Wilder R.T.
    • Flick R.P.
    • Sprung J.
    • et al.
17. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009; 110: 796-804

    PubMed

    • Flick R.P.
    • Katusic S.K.
    • Colligan R.C.
    • et al.

18. Cognitive and behavioral outcomes after early exposure to

    to anesthesia and surgery. Pediatrics. 2011; 128: e1053-e1061
    • Bong C.L.
    • Allen J.C.
    • Kim J.T.
19. The effects of exposure to general anesthesia in infancy on academic performance at age 12. Anesth Analg. 2013; 117: 1419-1428

    PubMed

    • Backeljauw B.
    • Holland S.K.
    • Altaye M.
    • Loepke A.W.
20. Cognition and brain structure following early childhood surgery with anesthesia.Pediatrics. 2015; 136: e1-12

    PubMed

    • Mintz C.D.
    • Wagner M.
    • Loepke A.W.
21. Preclinical research into the effects of anesthetics on the developing brain: promises and pitfalls. J Neurosurg Anesthesiol. 2012; 24: 362-367

    PubMed

    • Hoffman W.E.
    • Kochs E.
    • Werner C.
    • Thomas C.
    • Albrecht R.F.
22. Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology. 1991; 75: 328-332

    PubMed

    • Duan X.
    • Li Y.
    • Zhou C.
    • Huang L.
    • Dong Z.
23. Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand. 2014; 58: 1121-1126

    PubMed

    • Sanders R.D.
    • Sun P.
    • Patel S.
    • Li M.
    • Maze M.
    • Ma D.
24. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010; 54: 710-716

    PubMed

    • Sanders R.D.
    • Xu J.
    • Shu Y.
    • et al.
25. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology. 2009; 110: 1077-1085

    PubMed

    • Perez-Zoghbi J.F.
    • Zhu W.
    • Grafe M.R.
    • Brambrink A.M.
26. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth. 2017; 119: 506-516
    • PubMed
    • Abstract
    • Full Text
    • Full Text PDF
    • Orliaguet G.
    • Vivien B.
    • Langeron O.
    • Bouhemad B.
    • Coriat P.
    • Riou B.
27. Minimum alveolar concentration of volatile anesthetics in rats during postnatal maturation. Anesthesiology. 2001; 95: 734-739
    • PubMed
    • Loepke A.W.
    • Istaphanous G.K.
    • McAuliffe 3rd, J.J.
    • et al.
28. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009; 108: 90-104
    • PubMed
    • Kilkenny C.
    • Browne W.J.
    • Cuthill I.C.
    • Emerson M.
    • Altman D.G.
29. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8e1000412
    • PubMed
    • Lee J.R.
    • Lin E.P.
    • Hofacer R.D.
    • et al.
30. Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats. Br J Anaesth. 2017; 119: 492-505
    • PubMed
    • Abstract
    • Full Text
    • Full Text PDF
    • Khazipov R.
    • Zaynutdinova D.
    • Ogievetsky E.
    • et al.
31. Atlas of the postnatal rat brain in stereotaxic coordinates. Front Neuroanat. 2015; 9: 161

    PubMed

    • Howell K.
    • Hopkins N.
    • McLoughlin P.
32. Combined confocal microscopy and stereology: a highly efficient and unbiased approach to quantitative structural measurement in tissues. Exp Physiol. 2002; 87: 747-756

    PubMed

    • Deng M.
    • Hofacer R.D.
    • Jiang C.
    • et al.
33. Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at exposure and extends into adulthood for some regions. Br J Anaesth. 2014; 113: 443-451

    AbstractFull Text

34. • Noguchi K.K.
    • Johnson S.A.
    • Dissen G.A.
    • et al.
35. Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain. Br J Anaesth. 2017; 119: 524-531

    PubMedAbstractFull TextFull Text PDF

    • Warner D.O.
    • Flick R.P.
36. Anaesthetics, infants, and neurodevelopment: case closed? Lancet. 2016; 387: 202-204

    PubMedAbstractFull TextFull Text PDF

    • Andropoulos D.B.
    • Greene M.F.
37. Anesthesia and developing brains—implications of the FDA warning. N Engl J Med. 2017; 376: 905-907
     PubMed
    • Lei S.Y.
    • Hache M.
    • Loepke A.W.
38. Clinical research into anesthetic neurotoxicity—does anesthesia cause neurological abnormalities in humans?. J Neurosurg Anesthesiol. 2014; 26: 349-357

    PubMed

    • Davidson A.J.
    • Sun L.S.
39. Clinical evidence for any effect of anesthesia on the developing brain. Anesthesiology. 2018; 128: 840-853
    • PubMed
    • Sanders R.D.
    • Andropoulos D.B.
    • Ma D.
    • Maze M.
40. Theseus, the labyrinth, and the minotaur of anaesthetic-induced developmental neurotoxicity. Br J Anaesth. 2017; 119: 453-455
    • PubMed
    • Full Text
    • Full Text PDF
    • Coté C.J.
41. Pediatric anesthesia. in: Miller R.D. Eriksson L.I. Fleisher L.A. Wiener-Kronish J.P. Cohen N.H. Young W.L. Miller’s Anesthesia. Elsevier Saunders, Philadelphia, PA2014: 2757-2798
    • Reagan-Shaw S.
    • Nihal M.
    • Ahmad N.
42. Dose translation from animal to human studies revisited. FASEB J. 2008; 22: 659-661

    PubMed

    • Hofacer R.D.
    • Deng M.
    • Ward C.G.
    • et al.
43. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013; 73: 695-704
    • PubMed
    • Atluri N.
    • Joksimovic S.M.
    • Oklopcic A.
    • et al.
44. A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain. Br J Anaesth. 2018; 120: 768-778
    • Full Text
    • Full Text PDF

     PubMed

    • Lee B.H.
    • Hazarika O.D.
    • Quitoriano G.R.
    • et al.
45. Effect of combining anesthetics in neonates on long-term cognitive function. Int J Dev Neurosci. 2014; 37: 87-93

    PubMed

    • Szmuk P.
    • Andropoulos D.
    • McGowan F.
    • et al.
46. An open label pilot study of a dexmedetomidine-remifentanil-caudal anesthetic for infant lower abdominal/lower extremity surgery: the T REX pilot study. Paediatr Anaesth. 2019; 29: 59-67

    PubMed

    • Loepke A.W.
    • McCann J.C.
    • Kurth C.D.
    • McAuliffe J.J.
47. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth Analg. 2006; 102: 75-80

    PubMed

    • Liu J.R.
    • Yuki K.
    • Baek C.
    • Han X.H.
    • Soriano S.G.
48. Dexmedetomidine-induced neuroapoptosis is dependent on its cumulative dose. Anesth Analg. 2016; 123: 1008-1017

    PubMed

    • Creeley C.
    • Dikranian K.
    • Dissen G.
    • Martin L.
    • Olney J.
    • Brambrink A.
49. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 2013; 110: i29-38

    PubMedFull TextFull Text PDF

    • Shu Y.
    • Zhou Z.
    • Wan Y.
    • et al.
50. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol Dis. 2012; 45: 743-750

    PubMed

    • Broad K.D.
    • Kawano G.
    • Fierens I.
    • et al.

51.  

    • PubMed
      Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain. PLoS One. 2017; 12e0173413
    • Ju L.S.
    • Yang J.J.
    • Gravenstein N.
    • et al.
52. Role of environmental stressors in determining the developmental outcome of neonatal anesthesia. Psychoneuroendocrinology. 2017; 81: 96-104

    PubMed

    • Anand K.J.
    • Garg S.
    • Rovnaghi C.R.
    • Narsinghani U.
    • Bhutta A.T.
    • Hall R.W.

53. PubMed

    Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res. 2007; 62: 283-290
    • Liu J.R.
    • Liu Q.
    • Li J.
    • et al.

54.  

    • PubMed
      Noxious stimulation attenuates ketamine-induced neuroapoptosis in the developing rat brain. Anesthesiology. 2012; 117: 64-71
    • Shih J.
    • May L.D.
    • Gonzalez H.E.
    • et al.

55.  

    • PubMed
      Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology. 2012; 116: 586-602
    • Tong D.
    • Godale C.M.
    • Kadakia F.K.
    • et al.
56. Immature murine hippocampal neurones do not develop long-term structural changes after a single isoflurane exposure. Br J Anaesth. 2019; 123: 818-826

    Full TextFull Text PDF

    • Workman A.D.
    • Charvet C.J.
    • Clancy B.
    • Darlington R.B.
    • Finlay B.L.
57. Modeling transformations of neurodevelopmental sequences across mammalian species. J Neurosci. 2013; 33: 7368-7383

    PubMed

Print PDF

• Related Studies :

  • Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction.

    Using Sprague-Dawley rats and rat PC12 cells treated with sodium fluoride (NaF), we investigated the effects of SIK2-CRTC1 signaling on the neurobehavioral toxicity induced by fluoride. The in vivo results demonstrated that NaF treatment induced anxiety- and depression-like behaviors in juvenile rats, resulting in histological and ultrastructural abnormalities in the

  • Molecular mechanism of brain impairment caused by drinking-acquired fluorosis and selenium intervention

    This study investigated the molecular mechanism of brain impairment induced by drinking fluoridated water and selenium intervention. Results showed that the learning and memory of rats in NaF group significantly decreased. Moreover, the number of apoptotic cells, the expression levels of Cytc mRNA and protein, and the expression levels of

  • Changed expressions of N-methyl-D-aspartate receptors in the brains of rats and primary neurons exposed to high level of fluoride

    Expressions of N-methyl-d-aspartic acid receptors (NMDARs) in the brains of rats and primary neurons exposed to high fluoride were investigated. Sprague-Dawley rats were divided randomly into a fluorosis group (50 ppm fluoride in the drinking water for 6 months) and controls (<0.5ppm fluoride) and the offspring from these rats sacrificed

  • Effects of NaF on the expression of intracellular Ca2+ fluxes and apoptosis and the antagonism of taurine in murine neuron

    Sodium fluoride (NaF) has been shown to be cytotoxic and produces inflammatory responses in humans. However, the cellular mechanisms underlying the neurotoxicity of fluoride are unclear. The present study aims to define a possible mechanism of NaF-induced neurotoxicity with respect to apoptosis and intracellular Ca(2+) fluxes. Meanwhile, the cytoprotective role

  • Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children.

    Fluoride neurotoxicity is associated with mitochondrial disruption. Mitochondrial fission/fusion dynamics is crucial to maintain functional mitochondria, yet little is known about how fluoride perturbs this dynamics and whether such perturbation contributes to impaired neurodevelopment. Here in human neuroblastoma SH-SY5Y cells treated with sodium fluoride (NaF, 20, 40 and 60 mg/L), mitochondrial

• Related FAN Content :

  • Fluoride's Effect on Fetal Brain

    The human placenta does not prevent the passage of fluoride from a pregnant mother's bloodstream to the fetus. As a result, a fetus can be harmed by fluoride ingested pregnancy. Based on research from China, the fetal brain is one of the organs susceptible to fluoride poisoning. As highlighted by the excerpts

  • Fluoride: Developmental Neurotoxicity.

    Developmental Neurotoxicity There has been a tremendous amount of research done on the association of exposure to fluoride with developmental neurotoxicity. There are over 60 studies reporting reduced IQ in children and several on the impaired learning/memory in animals. And there are studies which link fluoride to Attention Deficit Hyperactivity Disorder. Teaching

  • Fluoride Affects Learning & Memory in Animals

    An association between elevated fluoride exposure and reduced intelligence has now been observed in 65 IQ studies. Although a link between fluoride and intelligence might initially seem surprising or random, it is actually consistent with a large body of animal research. This animal research includes the following 45 studies (out

  • Fluoride's Direct Effects on Brain: Animal Studies

    The possibility that fluoride ingestion may impair intelligence and other indices of neurological function is supported by a vast body of animal research, including over 40 studies that have investigated fluoride's effects on brain quality in animals. As discussed by the National Research Council, the studies have consistently demonstrated that fluoride, at widely varying concentrations, is toxic to the brain.

  • Fluoride & IQ: 76 Studies

    Note: See the Updated list of fluoride IQ studies at https://fluoridealert.org/researchers/fluoride-iq-studies/the-fluoride-iq-studies/ • As of July 18, 2022, a total of 85 human studies have investigated the relationship between fluoride and human intelligence. • Of these investigations, 76 studies have reported that elevated fluoride exposure is associated with reduced IQ in humans. • The studies