Advertisement

Neurocritical Care

, Volume 29, Issue 3, pp 496–503 | Cite as

Cerebral Metabolic Changes Related to Oxidative Metabolism in a Model of Bacterial Meningitis Induced by Lipopolysaccharide

  • M. Munk
  • F. R. Poulsen
  • L. Larsen
  • C. H. Nordström
  • T. H. Nielsen
Translational research

Abstract

Background

Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis.

Methods

Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO2) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O2 and CO2. Pigs were monitored for 60 min at baseline and 240 min after LPS/NaCl injection.

Results

After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (p = 0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO2 or ICP was registered. No changes in physiological variables were observed.

Conclusions

The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO2, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring.

Keywords

Meningitis Lipopolysaccharide Microdialysis Mitochondrial dysfunction 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12028_2018_509_MOESM1_ESM.jpg (226 kb)
Supplementary Fig. 1 Glutamate and glycerol at baseline (0-60 min) and after LPS or NaCl injection in the LPS and Control group respectively. For glutamate, no difference from baseline was found in either group. Glycerol tended to increase in the LPS group after LPS injection. The increase was not significant (JPEG 226 kb)

References

  1. 1.
    Edberg M, Furebring M, Sjolin J, Enblad P. Neurointensive care of patients with severe community-acquired meningitis. Acta Anaesthesiol Scand. 2011;55(6):732–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Auburtin M, Porcher R, Bruneel F, Scanvic A, Trouillet JL, Bedos JP, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit Care Med. 2002;165(5):713–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Liechti FD, Grandgirard D, Leib SL. Bacterial meningitis: insights into pathogenesis and evaluation of new treatment options: a perspective from experimental studies. Future Microbiol. 2015;10(7):1195–213.CrossRefPubMedGoogle Scholar
  4. 4.
    Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002;186(Suppl 2):S225–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Gerber J, Nau R. Mechanisms of injury in bacterial meningitis. Curr Opin Neurol. 2010;23(3):312–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Lucas MJ, Brouwer MC, van de Beek D. Neurological sequelae of bacterial meningitis. J Infect. 2016;73(1):18–27.CrossRefPubMedGoogle Scholar
  7. 7.
    Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2015(9):CD004405.Google Scholar
  8. 8.
    Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, et al. Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis. 2016;16(3):339–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Barichello T, Savi GD, Simoes LR, Generoso JS, Fraga DB, Bellettini G, et al. Evaluation of mitochondrial respiratory chain in the brain of rats after pneumococcal meningitis. Brain Res Bull. 2010;82(5–6):302–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Poulsen FR, Schulz M, Jacobsen A, Andersen AB, Larsen L, Schalen W, et al. Bedside Evaluation of Cerebral Energy Metabolism in Severe Community-Acquired Bacterial Meningitis. Neurocrit Care. 2015;22(2):221–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Temesvari P, Abraham CS, Speer CP, Kovacs J, Megyeri P. Escherichia coli 0111 B4 lipopolysaccharide given intracisternally induces blood-brain barrier opening during experimental neonatal meningitis in piglets. Pediatr Res. 1993;34(2):182–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Tunkel AR, Rosser SW, Hansen EJ, Scheld WM. Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide. Vitro Cell Dev Biol. 1991;27A(2):113–20.CrossRefGoogle Scholar
  13. 13.
    Noh H, Jeon J, Seo H. Systemic injection of LPS induces region-specific neuroinflammation and mitochondrial dysfunction in normal mouse brain. Neurochem Int. 2014;69:35–40.CrossRefPubMedGoogle Scholar
  14. 14.
    Yao SY, Natarajan C, Sriram S. nNOS mediated mitochondrial injury in LPS stimulated oligodendrocytes. Mitochondrion. 2012;12(2):336–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Chuang YC, Tsai JL, Chang AY, Chan JY, Liou CW, Chan SH. Dysfunction of the mitochondrial respiratory chain in the rostral ventrolateral medulla during experimental endotoxemia in the rat. J Biomed Sci. 2002;9(6 Pt 1):542–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Gardenfors A, Nilsson F, Skagerberg G, Ungerstedt U, Nordstrom CH. Cerebral physiological and biochemical changes during vasogenic brain oedema induced by intrathecal injection of bacterial lipopolysaccharides in piglets. Acta Neurochir (Wien). 2002;144(6):601-8; discussion 8-9.Google Scholar
  17. 17.
    Burroughs M, Cabellos C, Prasad S, Tuomanen E. Bacterial components and the pathophysiology of injury to the blood-brain barrier: does cell wall add to the effects of endotoxin in gram-negative meningitis? J Infect Dis. 1992;165(Suppl 1):S82–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM. Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest. 1988;82(4):1339–46.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, Nordstrom CH. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery. 2000;47(3):701-9; discussion 9-10.Google Scholar
  20. 20.
    Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordstrom CH. Cerebral energy metabolism during induced mitochondrial dysfunction. Acta Anaesthesiol Scand. 2013;57(2):229–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Nielsen TH, Olsen NV, Toft P, Nordstrom CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand. 2013;57(6):793–801.CrossRefPubMedGoogle Scholar
  22. 22.
    Nordstrom CH, Nielsen TH, Schalen W, Reinstrup P, Ungerstedt U. Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion. Acta Neurochir (Wien). 2016;158(7):1231–40.CrossRefGoogle Scholar
  23. 23.
    Jacobsen A, Nielsen TH, Nilsson O, Schalen W, Nordstrom CH. Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand. 2014;130(3):156–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Nielsen TH, Schalen W, Stahl N, Toft P, Reinstrup P, Nordstrom CH. Bedside Diagnosis of Mitochondrial Dysfunction After Malignant Middle Cerebral Artery Infarction. Neurocrit Care. 2014;21(1):35–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Rosenthal G, Hemphill JC 3rd, Manley G. Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care Med. 2009;37(1):379–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Pennings FA, Schuurman PR, van den Munckhof P, Bouma GJ. Brain tissue oxygen pressure monitoring in awake patients during functional neurosurgery: the assessment of normal values. J Neurotrauma. 2008;25(10):1173–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Nielsen TH, Engell SI, Johnsen RA, Schulz MK, Gerke O, Hjelmborg J, et al. Comparison Between Cerebral Tissue Oxygen Tension and Energy Metabolism in Experimental Subdural Hematoma. Neurocrit Care. 2011;15(3):585–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Jungner M, Bentzer P, Grande PO. Intracranial pressure following resuscitation with albumin or saline in a cat model of meningitis. Crit Care Med. 2011;39(1):135–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Kaizaki A, Tien LT, Pang Y, Cai Z, Tanaka S, Numazawa S, et al. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. J Neuroinflammation. 2013;10:45.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Samuelsson C, Hillered L, Zetterling M, Enblad P, Hesselager G, Ryttlefors M, et al. Cerebral glutamine and glutamate levels in relation to compromised energy metabolism: a microdialysis study in subarachnoid hemorrhage patients. J Cereb Blood Flow Metab. 2007;27(7):1309–17.CrossRefPubMedGoogle Scholar
  31. 31.
    Ungerstedt U, Bäckström T, Hallstrom A. Microdialysis in normal and injured human brain. In: Kinney JM, Tucker HN, editors. Physiology, stress and malnutrition: functional correlates, nutritional intervention. New York: Lippincott-Raven; 1997. p. 361–74.Google Scholar
  32. 32.
    Hillered L, Valtysson J, Enblad P, Persson L. Interstitial glycerol as a marker for membrane phospholipid degradation in the acutely injured human brain. J Neurol Neurosurg Psychiatry. 1998;64(4):486–91.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238–42.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016;167(2):457-70 e13.Google Scholar
  35. 35.
    von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016;524(18):3865–95.CrossRefGoogle Scholar
  36. 36.
    Doll DN, Hu H, Sun J, Lewis SE, Simpkins JW, Ren X. Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier. Stroke. 2015;46(6):1681–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Larsen L, Poulsen FR, Nielsen TH, Nordstrom CH, Schulz MK, Andersen AB. Use of intracranial pressure monitoring in bacterial meningitis: a 10-year follow up on outcome and intracranial pressure versus head CT scans. Infect Dis (Lond). 2017;49(5):356–64.CrossRefPubMedGoogle Scholar
  38. 38.
    Barichello T, Collodel A, Generoso JS, Simoes LR, Moreira AP, Ceretta RA, et al. Targets for adjunctive therapy in pneumococcal meningitis. J Neuroimmunol. 2015;278:262–70.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University of Southern Denmark School of MedicineOdenseDenmark
  2. 2.Department of NeurosurgeryOdense University HospitalOdenseDenmark
  3. 3.Department of Infectious DiseasesOdense University HospitalOdenseDenmark
  4. 4.Department of NeurosurgeryStanford University School of MedicineStanfordUSA

Personalised recommendations