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Microdialysis patterns in subarachnoid hemorrhage patients with focus on ischemic events and brain interstitial glutamine levels

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Abstract

Background

This observational microdialysis (MD) study of 33 subarachnoid hemorrhage patients explores brain interstitial levels of glutamine, glutamate, lactate and pyruvate, and their relationship to clinical status and clinical course at the neurointensive care unit.

Methods

The focus was on ischemic events, defined by clinical criteria or by radiology, and the significance of brain interstitial glutamine levels and lactate/pyruvate (L/P) ratio.

Results

Eleven out of 12 periods with an ischemic MD pattern, defined as lactate/pyruvate (L/P) ratios exceeding 40, were either related to delayed ischemic neurological deficits (DIND) or CT-verified infarcts, confirming that L/P above 40 is a specific ischemic and pathological MD measure. Poor admittance WFNS grade (WFNS 4–5) patients had lower glutamine at the onset of monitoring than what good admittance WFNS grade (WFNS 1–3) patients had (P < 0.05). Interstitial glutamine increased over time in most patients. A “glutamine surge” was defined as a period where the interstitial glutamine concentration increased at least 150 μM over 12 h. Fifteen patients had a DIND and associated MD patterns were glutamine surges (n = 12) and/or L/P>40 (n = 6). Seven patients received vasospasm treatment; in five of these the only DIND-associated MD pattern was a glutamine surge. Seventy percent of the glutamine surges occurred during ongoing propofol sedation, and there was no association between extubations and glutamine surges. There was no difference in mean glutamine levels during the monitoring period between patients with favorable 6-month outcome and patients with poor 6-month outcome.

Conclusion

We suggest that an increasing interstitial glutamine trend is a dynamic sign of augmented astrocytic metabolism with accelerated glutamate uptake and glutamine synthesis. This pattern is presumably present in metabolically challenged, but yet not overt ischemic tissue.

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Abbreviations

CPP:

cerebral perfusion pressure

CSF:

cerebrospinal fluid

CT:

computed tomography

Gln:

glutamine

Glt:

glutamate

GMS:

Glasgow Motor Score

GOS:

Glasgow Outcome Scale

HPLC:

high performance liquid chromatography

ICP:

intracranial pressure

L/P:

lactate/pyruvate ratio

MAP:

mean arterial pressure

MD:

microdialysis

NICU:

neurointensive care unit

RLS:

Reaction Level Scale

SAH:

subarachnoid hemorrhage

SD:

standard deviation

TBI:

traumatic brain injury

TCA:

tricarboxylic acid

VD:

ventricular drain

WFNS:

World Federation of Neurological Surgeons

References

  1. Borg J, Britton M, Colliander M, Ericson K af Geijerstam J, Marke L, Nathorst Westfelt J, Oredsson S, Ronne Engstrom E (2000) Hjärnskakning -övervakning på sjukhus eller datortomografi och hemgång, The Swedish Council on Technology Assesment in Health Care, Stockholm, p 26

  2. Broer S, Brookes N (2001) Transfer of glutamine between astrocytes and neurons. J Neurochem 77:705–719. doi:10.1046/j.1471-4159.2001.00322.x

    Article  PubMed  CAS  Google Scholar 

  3. Cesarini KG, Enblad P, Ronne-Engstrom E, Marklund N, Salci K, Nilsson P, Hardemark HG, Hillered L, Persson L (2002) Early cerebral hyperglycolysis after subarachnoid haemorrhage correlates with favourable outcome. Acta Neurochir (Wien) 144:1121–1131. doi:10.1007/s00701-002-1011-9

    Article  CAS  Google Scholar 

  4. Dohmen C, Bosche B, Graf R, Staub F, Kracht L, Sobesky J, Neveling M, Brinker G, Heiss WD (2003) Prediction of malignant course in MCA infarction by PET and microdialysis. Stroke 34:2152–2158. doi:10.1161/01.STR.0000083624.74929.32

    Article  PubMed  Google Scholar 

  5. Gorovits R, Avidan N, Avisar N, Shaked I, Vardimon L (1997) Glutamine synthetase protects against neuronal degeneration in injured retinal tissue. Proc Natl Acad Sci USA 94:7024–7029. doi:10.1073/pnas.94.13.7024

    Article  PubMed  CAS  Google Scholar 

  6. Hamann M, Rossi DJ, Marie H, Attwell D (2002) Knocking out the glial glutamate transporter GLT-1 reduces glutamate uptake but does not affect hippocampal glutamate dynamics in early simulated ischaemia. Eur J Neurosci 15:308–314. doi:10.1046/j.0953-816x.2001.01861.x

    Article  PubMed  Google Scholar 

  7. Hamberger AC, Chiang GH, Nylen ES, Scheff SW, Cotman CW (1979) Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate. Brain Res 168:513–530. doi:10.1016/0006-8993(79)90306-8

    Article  PubMed  CAS  Google Scholar 

  8. Hillered L, Hallstrom A, Segersvard S, Persson L, Ungerstedt U (1989) Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab 9:607–616

    PubMed  CAS  Google Scholar 

  9. Hillered L, Persson L, Nilsson P, Ronne-Engstrom E, Enblad P (2006) Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis. Curr Opin Crit Care 12:112–118. doi:10.1097/01.ccx.0000216576.11439.df

    Article  PubMed  Google Scholar 

  10. Hillered L, Persson L, Ponten U, Ungerstedt U (1990) Neurometabolic monitoring of the ischaemic human brain using microdialysis. Acta Neurochir (Wien) 102:91–97. doi:10.1007/BF01405420

    Article  CAS  Google Scholar 

  11. Hillered L, Vespa PM, Hovda DA (2005) Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. J Neurotrauma 22:3–41. doi:10.1089/neu.2005.22.3

    Article  PubMed  Google Scholar 

  12. Hlatky R, Valadka AB, Goodman JC, Robertson CS (2004) Evolution of brain tissue injury after evacuation of acute traumatic subdural hematomas. Neurosurgery 55:1318–1323, discussion 1324. doi:10.1227/01.NEU.0000143029.42638.2C

    Article  PubMed  Google Scholar 

  13. Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. Lancet 1:480–484. doi:10.1016/S0140-6736(75)92830-5

    Article  PubMed  CAS  Google Scholar 

  14. Johnston AJ, Gupta AK (2002) Advanced monitoring in the neurology intensive care unit: microdialysis. Curr Opin Crit Care 8:121–127. doi:10.1097/00075198-200204000-00006

    Article  PubMed  Google Scholar 

  15. Kanamori K, Ross BD (2004) Quantitative determination of extracellular glutamine concentration in rat brain, and its elevation in vivo by system A transport inhibitor, alpha-(methylamino)isobutyrate. J Neurochem 90:203–210. doi:10.1111/j.1471-4159.2004.02478.x

    Article  PubMed  CAS  Google Scholar 

  16. Kanamori K, Ross BD, Kondrat RW (2002) Glial uptake of neurotransmitter glutamate from the extracellular fluid studied in vivo by microdialysis and (13)C NMR. J Neurochem 83:682–695. doi:10.1046/j.1471-4159.2002.01161.x

    Article  PubMed  CAS  Google Scholar 

  17. Koura SS, Doppenberg EM, Marmarou A, Choi S, Young HF, Bullock R (1998) Relationship between excitatory amino acid release and outcome after severe human head injury. Acta Neurochir Suppl (Wien) 71:244–246

    CAS  Google Scholar 

  18. Magistretti PJ, Pellerin L (1999) Astrocytes couple synaptic activity to glucose utilization in the brain. News Physiol Sci 14:177–182

    PubMed  CAS  Google Scholar 

  19. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497. doi:10.1126/science.283.5401.496

    Article  PubMed  CAS  Google Scholar 

  20. Meyerson BA, Linderoth B, Karlsson H, Ungerstedt U (1990) Microdialysis in the human brain: extracellular measurements in the thalamus of parkinsonian patients. Life Sci 46:301–308. doi:10.1016/0024-3205(90)90037-R

    Article  PubMed  CAS  Google Scholar 

  21. Mitani A, Tanaka K (2003) Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. J Neurosci 23:7176–7182

    PubMed  CAS  Google Scholar 

  22. Nelson DW, Bellander BM, Maccallum RM, Axelsson J, Alm M, Wallin M, Weitzberg E, Rudehill A (2004) Cerebral microdialysis of patients with severe traumatic brain injury exhibits highly individualistic patterns as visualized by cluster analysis with self-organizing maps. Crit Care Med 32:2428–2436. doi:10.1097/01.CCM.0000147688.08813.9C

    Article  PubMed  CAS  Google Scholar 

  23. Nishizawa Y (2001) Glutamate release and neuronal damage in ischemia. Life Sci 69:369–381. doi:10.1016/S0024-3205(01)01142-0

    Article  PubMed  CAS  Google Scholar 

  24. Peerdeman SM, van Tulder MW, Vandertop WP (2003) Cerebral microdialysis as a monitoring method in subarachnoid hemorrhage patients, and correlation with clinical events–a systematic review. J Neurol 250:797–805. doi:10.1007/s00415-003-1079-z

    Article  PubMed  Google Scholar 

  25. Ramonet D, Rodriguez MJ, Fredriksson K, Bernal F, Mahy N (2004) In vivo neuroprotective adaptation of the glutamate/glutamine cycle to neuronal death. Hippocampus 14:586–594. doi:10.1002/hipo.10188

    Article  PubMed  CAS  Google Scholar 

  26. Richards DA, Tolias CM, Sgouros S, Bowery NG (2003) Extracellular glutamine to glutamate ratio may predict outcome in the injured brain: a clinical microdialysis study in children. Pharmacol Res 48:101–109

    PubMed  CAS  Google Scholar 

  27. Ronne Engstrom E, Hillered L, Enblad P, Karlsson T (2005) Cerebral interstitial levels of glutamate and glutamine after intravenous administration of nutritional amino acids in neurointensive care patients. Neurosci Lett 384:7–10. doi:10.1016/j.neulet.2005.04.030

    Article  PubMed  CAS  Google Scholar 

  28. Ronne-Engstrom E, Cesarini KG, Enblad P, Hesselager G, Marklund N, Nilsson P, Salci K, Persson L, Hillered L (2001) Intracerebral microdialysis in neurointensive care: the use of urea as an endogenous reference compound. J Neurosurg 94:397–402

    PubMed  CAS  Google Scholar 

  29. Sakowitz OW, Unterberg AW (2006) Detecting and treating microvascular ischemia after subarachnoid hemorrhage. Curr Opin Crit Care 12:103–111. doi:10.1097/01.ccx.0000216575.03815.ee

    Article  PubMed  Google Scholar 

  30. Samuelsson C, Hillered L, Zetterling M, Enblad P, Hesselager G, Ryttlefors M, Kumlien E, Lewen A, Marklund N, Nilsson P, Salci K, Ronne-Engstrom E (2007) Cerebral glutamine and glutamate levels in relation to compromised energy metabolism: a microdialysis study in subarachnoid hemorrhage patients. J Cereb Blood Flow Metab 27:1309–1317. doi:10.1038/sj.jcbfm.9600433

    Article  PubMed  CAS  Google Scholar 

  31. Samuelsson C, Howells T, Kumlien E, Enblad P, Hillered L, Ronne-Engstrom E Relationship between intracranial hemodynamics and microdialysis markers of energy metabolism and glutamate-glutamine turnover in subarachnoid hemorrhage patients. J Neurosurg (in press)

  32. Sarrafzadeh A, Haux D, Kuchler I, Lanksch WR, Unterberg AW (2004) Poor-grade aneurysmal subarachnoid hemorrhage: relationship of cerebral metabolism to outcome. J Neurosurg 100:400–406

    Article  PubMed  Google Scholar 

  33. Sarrafzadeh A, Haux D, Sakowitz O, Benndorf G, Herzog H, Kuechler I, Unterberg A (2003) Acute focal neurological deficits in aneurysmal subarachnoid hemorrhage: relation of clinical course, CT findings, and metabolite abnormalities monitored with bedside microdialysis. Stroke 34:1382–1388. doi:10.1161/01.STR.0000074036.97859.02

    Article  PubMed  CAS  Google Scholar 

  34. Sarrafzadeh AS, Sakowitz OW, Kiening KL, Benndorf G, Lanksch WR, Unterberg AW (2002) Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients? Crit Care Med 30:1062–1070. doi:10.1097/00003246-200205000-00018

    Article  PubMed  Google Scholar 

  35. Seki Y, Feustel PJ, Keller RW Jr, Tranmer BI, Kimelberg HK (1999) Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker. Stroke 30:433–440

    PubMed  CAS  Google Scholar 

  36. Skjoth-Rasmussen J, Schulz M, Kristensen SR, Bjerre P (2004) Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 100:8–15

    PubMed  CAS  Google Scholar 

  37. Stalhammar D, Starmark JE, Holmgren E, Eriksson N, Nordstrom CH, Fedders O, Rosander B (1988) Assessment of responsiveness in acute cerebral disorders. A multicentre study on the reaction level scale (RLS 85). Acta Neurochir (Wien) 90:73–80. doi:10.1007/BF01560558

    Article  CAS  Google Scholar 

  38. Suarez I, Bodega G, Fernandez B (2002) Glutamine synthetase in brain: effect of ammonia. Neurochem Int 41:123–142. doi:10.1016/S0197-0186(02)00033-5

    Article  PubMed  CAS  Google Scholar 

  39. Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348:443–446. doi:10.1038/348443a0

    Article  PubMed  CAS  Google Scholar 

  40. Teasdale G, Jennett B (1976) Assessment and prognosis of coma after head injury. Acta Neurochir (Wien) 34:45–55. doi:10.1007/BF01405862

    Article  CAS  Google Scholar 

  41. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, De Villiers JC (1988) A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 51:1457. doi:10.1136/jnnp.51.11.1457

    Article  PubMed  CAS  Google Scholar 

  42. Thanki CM, Sugden D, Thomas AJ, Bradford HF (1983) In vivo release from cerebral cortex of [14C]glutamate synthesized from [U-14C]glutamine. J Neurochem 41:611–617. doi:10.1111/j.1471-4159.1983.tb04785.x

    Article  PubMed  CAS  Google Scholar 

  43. Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA, Glenn TC, McArthur DL, Hovda DA (2005) Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 25:763–774. doi:10.1038/sj.jcbfm.9600073

    Article  PubMed  CAS  Google Scholar 

  44. Xie M, Wang W, Kimelberg HK, Zhou M (2007) Oxygen and glucose deprivation-induced changes in astrocyte membrane potential and their underlying mechanisms in acute rat hippocampal slices. J Cereb Blood Flow Metab

  45. Xu GY, McAdoo DJ, Hughes MG, Robak G, de Castro R Jr (1998) Considerations in the determination by microdialysis of resting extracellular amino acid concentrations and release upon spinal cord injury. Neuroscience 86:1011–1021. doi:10.1016/S0306-4522(98)00063-3

    Article  PubMed  CAS  Google Scholar 

  46. Yi JH, Hazell AS (2006) Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48:394–403. doi:10.1016/j.neuint.2005.12.001

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We are grateful to Inger Ståhl-Myllyaho for her expert work with the HPLC system and to the staff at the neurointensive care unit for care of the patients and collection of the MD samples.

Financial support has been obtained from the following contributors: Swedish Medical Research Council, grants 521–2004–6210 and 521–2007–3254, GlaxoSmithKline, the Margarethahemmet Foundation, the Erland Wessler Foundation, The Ahlén Foundation, the Selanders Foundation and Uppsala University Hospital.

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Authors and Affiliations

  1. Department of Neuroscience, Neurosurgery, Uppsala University Hospital, Uppsala, Sweden

    Carolina Samuelsson, Lars Hillered, Per Enblad & Elisabeth Ronne-Engström

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  1. Carolina Samuelsson
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  2. Lars Hillered
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Correspondence to Carolina Samuelsson.

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Comment

This paper addresses the field of neurochemistry that has not yet been fully understood. The paper is interesting, although the lactate/pyruvate ratio (L/P) has been addressed in multiple papers. The attempt to correlate L/P to clinical events, i.e., delayed ischemic neurological deficits (DIND), has been addressed in a few papers only, and yet there is no work using microdialysis patterns in an attempt to progressively forecast the ischemic events, which could bring microdialysis research further.

Overall, I find this paper well written and interesting, addressing in a very honest way the difficult field of cerebral metabolism in patients with aneurismal subarachnoid hemorrhage and delayed neurological deficits.

Jane Skjoth-Rasmussen

Rigshospitalet, Copenhagen

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Samuelsson, C., Hillered, L., Enblad, P. et al. Microdialysis patterns in subarachnoid hemorrhage patients with focus on ischemic events and brain interstitial glutamine levels. Acta Neurochir 151, 437–446 (2009). https://doi.org/10.1007/s00701-009-0265-x

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