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Bedside Diagnosis of Mitochondrial Dysfunction After Malignant Middle Cerebral Artery Infarction

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Abstract

Background

The study explores whether the cerebral biochemical pattern in patients treated with hemicraniectomy after large middle cerebral artery infarcts reflects ongoing ischemia or non-ischemic mitochondrial dysfunction.

Methods

The study includes 44 patients treated with decompressive hemicraniectomy (DCH) due to malignant middle cerebral artery infarctions. Chemical variables related to energy metabolism obtained by microdialysis were analyzed in the infarcted tissue and in the contralateral hemisphere from the time of DCH until 96 h after DCH.

Results

Reperfusion of the infarcted tissue was documented in a previous report. Cerebral lactate/pyruvate ratio (L/P) and lactate were significantly elevated in the infarcted tissue compared to the non-infarcted hemisphere (p < 0.05). From 12 to 96 h after DCH the pyruvate level was significantly higher in the infarcted tissue than in the non-infarcted hemisphere (p < 0.05).

Conclusion

After a prolonged period of ischemia and subsequent reperfusion, cerebral tissue shows signs of protracted mitochondrial dysfunction, characterized by a marked increase in cerebral lactate level with a normal or increased cerebral pyruvate level resulting in an increased LP-ratio. This biochemical pattern contrasts to cerebral ischemia, which is characterized by a marked decrease in cerebral pyruvate. The study supports the hypothesis that it is possible to diagnose cerebral mitochondrial dysfunction and to separate it from cerebral ischemia by microdialysis and bed-side biochemical analysis.

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References

  1. Engstrom M, Polito A, Reinstrup P, et al. Intracerebral microdialysis in severe brain trauma: the importance of catheter location. J Neurosurg. 2005;102:460–9.

    Article  PubMed  Google Scholar 

  2. Nordstrom CH. Cerebral energy metabolism and microdialysis in neurocritical care. Childs Nerv Syst. 2010;26:465–72.

    Article  PubMed  Google Scholar 

  3. Niizuma K, Endo H, Chan PH. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem. 2009;109(Suppl 1):133–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Chen HI, Stiefel MF, Oddo M, et al. Detection of cerebral compromise with multimodality monitoring in patients with subarachnoid hemorrhage. Neurosurgery. 2011;69:53–63.

    Article  PubMed  Google Scholar 

  5. Vespa P, Bergsneider M, Hattori N, et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 2005;25:763–74.

    CAS  PubMed  Google Scholar 

  6. Vespa PM, O’Phelan K, McArthur D, et al. Pericontusional brain tissue exhibits persistent elevation of lactate/pyruvate ratio independent of cerebral perfusion pressure. Crit Care Med. 2007;35:1153–60.

    PubMed  Google Scholar 

  7. Rehncrona S, Mela L, Siesjo BK. Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia. Stroke. 1979;10:437–46.

    CAS  PubMed  Google Scholar 

  8. Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma. 2000;17:843–55.

    CAS  PubMed  Google Scholar 

  9. Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg. 2000;93:815–20.

    CAS  PubMed  Google Scholar 

  10. Robertson CL. Mitochondrial dysfunction contributes to cell death following traumatic brain injury in adult and immature animals. J Bioenerg Biomembr. 2004;36:363–8.

    CAS  PubMed  Google Scholar 

  11. Kilbaugh TJ, Bhandare S, Lorom DH, Saraswati M, Robertson CL, Margulies SS. Cyclosporin A preserves mitochondrial function after traumatic brain injury in the immature rat and piglet. J Neurotrauma. 2011;28:763–74.

    PubMed Central  PubMed  Google Scholar 

  12. Alessandri B, Rice AC, Levasseur J, DeFord M, Hamm RJ, Bullock MR. Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J Neurotrauma. 2002;19:829–41.

    PubMed  Google Scholar 

  13. Uchino H, Elmer E, Uchino K, et al. Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat. Brain Res. 1998;812:216–26.

    CAS  PubMed  Google Scholar 

  14. Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordstrom CH. Cerebral energy metabolism during induced mitochondrial dysfunction. Acta Anaesthesiol Scand. 2013;57:229–35.

    CAS  PubMed  Google Scholar 

  15. Nielsen TH, Olsen NV, Toft P, Nordstrom CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand. 2013;57:793–801.

    CAS  PubMed  Google Scholar 

  16. Nordstrom CH, Siesjo BK. Effects of phenobarbital in cerebral ischemia. Part I: cerebral energy metabolism during pronounced incomplete ischemia. Stroke. 1978;9:327–35.

    CAS  PubMed  Google Scholar 

  17. Stahl N, Mellergard P, Hallstrom A, Ungerstedt U, Nordstrom CH. Intracerebral microdialysis and bedside biochemical analysis in patients with fatal traumatic brain lesions. Acta Anaesthesiol Scand. 2001;45:977–85.

    CAS  PubMed  Google Scholar 

  18. Siesjö BK. Brain energy metabolism. Chichester,[Eng.]; New York: Wiley; 1978.

  19. Nielsen TH, Stahl N, Schalen W, Reinstrup P, Toft P, Nordstrom CH. Recirculation usually precedes malignant edema in middle cerebral artery infarcts. Acta Neurol Scand. 2012;126:404–10.

    CAS  PubMed  Google Scholar 

  20. 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;47:701–9 discussion 9-10.

    CAS  PubMed  Google Scholar 

  21. Pettersen JC, Cohen SD. The effects of cyanide on brain mitochondrial cytochrome oxidase and respiratory activities. J Appl Toxicol. 1993;13:9–14.

    CAS  PubMed  Google Scholar 

  22. Bains R, Moe MC, Vinje ML, Berg-Johnsen J. Sevoflurane and propofol depolarize mitochondria in rat and human cerebrocortical synaptosomes by different mechanisms. Acta Anaesthesiol Scand. 2009;53:1354–60.

    CAS  PubMed  Google Scholar 

  23. Bains R, Moe MC, Larsen GA, Berg-Johnsen J, Vinje ML. Volatile anaesthetics depolarize neural mitochondria by inhibition of the electron transport chain. Acta Anaesthesiol Scand. 2006;50:572–9.

    CAS  PubMed  Google Scholar 

  24. Vary TC. Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate. Shock. 1996;6:89–94.

    CAS  PubMed  Google Scholar 

  25. Amer-Wahlin I, Nord A, Bottalico B, et al. Fetal cerebral energy metabolism and electrocardiogram during experimental umbilical cord occlusion and resuscitation. J Matern Fetal Neonatal Med. 2010;23:158–66.

    CAS  PubMed  Google Scholar 

  26. 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;144:601–8 discussion 8-9.

    CAS  Google Scholar 

  27. Nordstrom CH, Rehncrona S, Siesjo BK. Effects of phenobarbital in cerebral ischemia. Part II: restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after pronounced incomplete ischemia. Stroke. 1978;9:335–43.

    CAS  PubMed  Google Scholar 

  28. Nordstrom CH, Rehncrona S, Siesjo BK. Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after 30 minutes of complete ischemia in rats anaesthetized with nitrous oxide or phenobarbital. J Neurochem. 1978;30:479–86.

    CAS  PubMed  Google Scholar 

  29. Norberg K, Siesjo BK. Cerebral metabolism in hypoxic hypoxia. I. Pattern of activation of glycolysis: a re-evaluation. Brain Res. 1975;86:31–44.

    CAS  PubMed  Google Scholar 

  30. Chapman AG, Meldrum BS, Siesjo BK. Cerebral metabolic changes during prolonged epileptic seizures in rats. J Neurochem. 1977;28:1025–35.

    CAS  PubMed  Google Scholar 

  31. Larach DB, Kofke WA, Le Roux P. Potential non-hypoxic/ischemic causes of increased cerebral interstitial fluid lactate/pyruvate ratio: a review of available literature. Neurocrit Care. 2011;15:609–22.

    PubMed  Google Scholar 

  32. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011;31:17–35.

    PubMed Central  PubMed  Google Scholar 

  33. Nakamura H, Strong AJ, Dohmen C, et al. Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain. 2010;133:1994–2006.

    PubMed Central  PubMed  Google Scholar 

  34. Hashemi P, Bhatia R, Nakamura H, et al. Persisting depletion of brain glucose following cortical spreading depression, despite apparent hyperaemia: evidence for risk of an adverse effect of Leao’s spreading depression. J Cereb Blood Flow Metab. 2009;29:166–75.

    CAS  PubMed  Google Scholar 

  35. Feuerstein D, Manning A, Hashemi P, et al. Dynamic metabolic response to multiple spreading depolarizations in patients with acute brain injury: an online microdialysis study. J Cereb Blood Flow Metab. 2010;30:1343–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Hopwood SE, Parkin MC, Bezzina EL, Boutelle MG, Strong AJ. Transient changes in cortical glucose and lactate levels associated with peri-infarct depolarisations, studied with rapid-sampling microdialysis. J Cereb Blood Flow Metab. 2005;25:391–401.

    CAS  PubMed  Google Scholar 

  37. Reinstrup P, Nordstrom CH. Prostacyclin infusion may prevent secondary damage in pericontusional brain tissue. Neurocrit Care. 2011;14:441–6.

    CAS  PubMed  Google Scholar 

  38. Vink R, Nimmo AJ, Cernak I. An overview of new and novel pharmacotherapies for use in traumatic brain injury. Clin Exp Pharmacol Physiol. 2001;28:919–21.

    CAS  PubMed  Google Scholar 

  39. Hwang JH, Lee JH, Lee KH, et al. Cyclosporine A attenuates hypoxic-ischemic brain injury in newborn rats. Brain Res. 2010;1359:208–15.

    CAS  PubMed  Google Scholar 

  40. Piilgaard H, Witgen BM, Rasmussen P, Lauritzen M, Cyclosporine A. FK506, and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression. J Cereb Blood Flow Metab. 2011;31:1588–98.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank Katarina Nielsen, Department of Neurosurgery, Lund University Hospital, for help with the microdialysis equipment and biochemical analyses. The study was supported by Grants from Lund University Hospital, Odense University Hospital and University of Southern Denmark.

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Correspondence to T. H. Nielsen.

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Nielsen, T.H., Schalén, W., Ståhl, N. et al. Bedside Diagnosis of Mitochondrial Dysfunction After Malignant Middle Cerebral Artery Infarction. Neurocrit Care 21, 35–42 (2014). https://doi.org/10.1007/s12028-013-9875-5

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