Skip to main content

Selective induction of IL-1β after a brief isoflurane anesthetic in children undergoing MRI examination

A Letter to the Editor to this article was published on 16 February 2017

Abstract

Purpose

To determine if isoflurane anesthesia without surgery causes systemic inflammation in children. Inflammation is targeted as responsible for the development of many neurologic pathologies. The effect will be evaluated by measuring serum cytokine levels before and after isoflurane anesthesia. The possible neurotoxic effect of anesthetic agents is a concern in pediatric anesthesia. Questions remain as to the true effects of anesthesia alone on systemic inflammation. The current study assesses systemic inflammatory response to general anesthesia in children not exposed to surgical stress.

Methods

Twenty-five patients, aged 6 months to 11 years undergoing MRI scanning were recruited. Patients with ASA Physical Status Classification >II, known neurologic disease, prematurity, recent infection, or current treatment with anti-inflammatory medications were excluded. Each patient received a sevoflurane induction, peripheral intravenous catheterization, and laryngeal mask airway placement. Isoflurane was titrated to ensure adequate depth of anesthesia. Two peripheral blood samples were obtained: one immediately after placement of the PIV and one upon arrival to the post-anesthesia care unit. Serum cytokine levels were compared between pre- and post-isoflurane time points using paired t tests.

Results

For all patients, interleukin-1β increased after isoflurane when compared to pre-isoflurane samples (pre = 25.97 ± 9.01, post = 38.53 ± 16.56, p = 0.0002). Serum levels of IL-6 (pre = 2.28 ± 2.27, post = 2.04 ± 2.15, p = 0.146) and tumor necrosis factor-α (pre = 94.26 ± 18.07, post = 85.84 ± 12.12, p = 0.057) were not significantly changed. Interleukin-10 and vascular endothelial growth factor were undetectable in pre- and post-isoflurane samples at a minimum detection threshold of 6.6 and 10 pg/ml, respectively.

Conclusions

A brief (approximately 60 min) exposure to isoflurane general anesthesia, without induced surgical stress, significantly increased serum IL-1β, a selective activation marker of systemic inflammation (IL-1β pathway).

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Davidson AJ, Disma N, De Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P. 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(10015):239–50.

    Article  PubMed  Google Scholar 

  3. 3.

    Disma N, Mondardini MC, Terrando N, Absalom AR, Bilotta F. A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research. Paediatr Anaesth. 2016;26:6–36.

    Article  PubMed  Google Scholar 

  4. 4.

    Whitaker EE, Bissonnette B, Miller AD, Koppert TL, Tobias JD, Pierson CR, Christofi FL. A novel, clinically relevant use of a piglet model to study the effects of anesthetics on the developing brain. Clin Trans Med. 2016;5(1):1.

    Article  Google Scholar 

  5. 5.

    Wagner M, Ryu YK, Smith SC, Mintz CD. Review: effects of anesthetics on brain circuit formation. J Neurosurg Anesthesiol. 2014;26:358–62.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Jackson WM, Gray CD, Jiang D, Schaefer ML, Connor C, Mintz CD. Molecular mechanisms of anesthetic neurotoxicity: a review of the current literature. J Neurosurg Anesthesiol. 2016;28:361–72.

    Article  PubMed  Google Scholar 

  7. 7.

    Zhang L, Zhang J, Yang L, Dong Y, Zhang Y, Xie Z. Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells. Br J Anaesth. 2013;110(Suppl 1):i82–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wu X, Lu Y, Dong Y, Zhang G, Zhang Y, Xu Z, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-alpha, IL-6, and IL-1beta. Neurobiol Aging. 2012;33:1364–78.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Hagberg H, Gressens P, Mallard C. Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol. 2012;71:444–57.

    Article  PubMed  Google Scholar 

  10. 10.

    Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Madore C, Leyrolle Q, Lacabanne C, Benmamar-Badel A, Joffre C, Nadjar A, Layé S. Neuroinflammation in Autism: plausible role of maternal inflammation, dietary omega 3, and microbiota. Neural Plast. 2016;2016:3597209.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Riedel B, Browne K, Silbert B. Cerebral protection: inflammation, endothelial dysfunction, and postoperative cognitive dysfunction. Curr Opin Anaesthesiol. 2014;27:89–97.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Peng L, Xu L, Ouyang W. Role of peripheral inflammatory markers in postoperative cognitive dysfunction (POCD): a meta-analysis. PLoS One. 2013;8:e79624.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Chawla BK, Teitelbaum DH. Profound systemic inflammatory response syndrome following non-emergent intestinal surgery in children. J Pediatr Surg. 2013;48:1936–40.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Haga Y, Beppu T, Doi K, Nozawa F, Mugita N, Ikei S, Ogawa M. Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery. Critical Care Med. 1997;25(12):1994–2000.

    CAS  Article  Google Scholar 

  16. 16.

    Stollings LM, Jia LJ, Tang P, Dou H, Lu B, Xu Y. Immune modulation by volatile anesthetics. Anesthesiology. 2016;125:399–411.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y, Xie Z. Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. J Am Soc Anesthesiol. 2013;118(3):502–15.

    CAS  Article  Google Scholar 

  18. 18.

    Shiihara T, Miyake T, Izumi S, Sugihara S, Watanabe M, Takanashi JI, Kubota M, Kato M. Serum and CSF biomarkers in acute pediatric neurological disorders. Brain Dev. 2014;36(6):489–95.

    Article  PubMed  Google Scholar 

  19. 19.

    Naureen I, Waheed KA, Rathore AW, Victor S, Mallucci C, Goodden JR, Chohan SN, Miyan JA. Fingerprint changes in CSF composition associated with different aetiologies in human neonatal hydrocephalus: inflammatory cytokines. Child’s Nerv Syst. 2014;30(7):1155–64.

    Article  Google Scholar 

  20. 20.

    Madhok AB, Ojamaa K, Haridas V, Parnell VA, Pahwa S, Chowdhury D. Cytokine response in children undergoing surgery for congenital heart disease. Pediatr Cardiol. 2006;27:408–13.

    Article  PubMed  Google Scholar 

  21. 21.

    Hansen TG, Tonnesen E, Andersen JB, Toft P, Bendtzen K. The peri-operative cytokine response in infants and young children following major surgery. Eur J Anaesthesiol. 1998;15:56–60.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Cardoso FL, Herz J, Fernandes A, Rocha J, Sepodes B, Brito MA, McGavern DB, Brites D. Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects. J Neuroinflam. 2015;12(1):1.

    Article  Google Scholar 

  23. 23.

    Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, Kuijlaars J, Langlois X, Matthews LJ, Ver Donck L, Hellings N. Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm. 2013;2013:271–359.

    Article  Google Scholar 

  24. 24.

    Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci USA. 2015;112:12468–73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Murta V, Farias MI, Pitossi FJ, Ferrari CC. Chronic systemic IL-1beta exacerbates central neuroinflammation independently of the blood-brain barrier integrity. J Neuroimmunol. 2015;278:30–43.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflam. 2012;9:151.

    CAS  Article  Google Scholar 

  27. 27.

    Malaeb S, Dammann O. Fetal inflammatory response and brain injury in the preterm newborn. J Child Neurol. 2009;24:1119–26.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Bianco-Batlles MD, Sosunov A, Polin RA, Ten VS. Systemic inflammation following hind-limb ischemia-reperfusion affects brain in neonatal mice. Dev Neurosci. 2008;30:367–73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Calderón-Garcidueñas L, Engle R, Mora-Tiscareño A, Styner M, Gómez-Garza G, Zhu H, Jewells V, Torres-Jardón R, Romero L, Monroy-Acosta ME, Bryant C. Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children. Brain Cogn. 2011;77(3):345–55.

    Article  PubMed  Google Scholar 

  30. 30.

    Saghazadeh A, Ferrari CC, Rezaei N. Deciphering variability in the role of interleukin-1beta in Parkinson’s disease. Rev Neurosci. 2016;27:635–50.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Won YH, Lee MY, Choi YC, Ha Y, Kim H, Kim DY, Kim MS, Yu JH, Seo JH, Kim M, Cho SR. Elucidation of relevant neuroinflammation mechanisms using gene expression profiling in patients with amyotrophic lateral sclerosis. PloS One. 2016;11(11):e0165290.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kolosowska K, Maciejak P, Szyndler J, Turzynska D, Sobolewska A, Plaznik A. The role of IL-1beta and glutamate in the effects of lipopolysaccharide on the hippocampal electrical kindling of seizures. J Neuroimmunol. 2016;298:146–52.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Mosher KI, Andres RH, Fukuhara T, Bieri G, Hasegawa-Moriyama M, He Y, Guzman R, Wyss-Coray T. Neural progenitor cells regulate microglia functions and activity. Nature Neurosci. 2012;15(11):1485–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Rothwell N, Allan S, Toulmond S. The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications. J Clin Invest. 1997;100:2648–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. NeuroImmunoModulation. 1995;2:241–8.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Wang XJ, Kong KM, Qi WL, Ye WL, Song PS. Interleukin-1 beta induction of neuron apoptosis depends on p38 mitogen-activated protein kinase activity after spinal cord injury. Acta Pharmacol Sin. 2005;26:934–42.

    Article  PubMed  Google Scholar 

  37. 37.

    Popić J, Pešić V, Milanović D, Lončarević-Vasiljković N, Smiljanić K, Kanazir S, Ruždijić S. Induction of TNF-α signaling cascade in neonatal rat brain during propofol anesthesia. Int J Dev Neurosci. 2015;44:22–32.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dmitry Tumin for his invaluable contribution to biostatistical analysis. The authors are also grateful to the nurses and colleagues in the radiology department for their support and generosity.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Emmett E. Whitaker.

Ethics declarations

Ethics approval

This study was approved by the Nationwide Children’s Hospital IRB on 1/20/2015 (#IRB14-00625, NCT02512809).

Funding

This study was generously supported by departmental start-up funds (EW), a Nationwide Children’s Hospital Intramural Grant (EW), and the Ohio State University Center for Clinical and Translational Science Davis-Bremer Pre-K Award (EW). This work was also supported in part by the OSU College of Medicine Roessler research scholarship (BW, JX). EW is also supported by an NIH LRP Grant, funded by the NIH NICHD to investigate potential neurotoxicity mechanisms of anesthetics in a neonatal piglet model. FLC is supported by R01 DK093499.

Conflict of interest

The authors have no conflicts of interest to report.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Whitaker, E.E., Christofi, F.L., Quinn, K.M. et al. Selective induction of IL-1β after a brief isoflurane anesthetic in children undergoing MRI examination. J Anesth 31, 219–224 (2017). https://doi.org/10.1007/s00540-016-2294-y

Download citation

Keywords

  • Pediatric anesthesia
  • Anesthesia-induced developmental neurotoxicity (AIDN)
  • Neuroinflammation
  • Isoflurane