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Stroke. 2004;35:e74-e76
Published online before print March 18, 2004, doi: 10.1161/01.STR.0000122621.36922.e1
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(Stroke. 2004;35:e74.)
© 2004 American Heart Association, Inc.

Letters to the Editor

In Vivo Regional Neurochemistry in Stroke: Clinical Applications, Limitations, and Future Directions

Anish Bhardwaj, MD

Neurosciences Critical Care Division, Johns Hopkins Hospital, Baltimore, Maryland

To the Editor:

I read with interest the article by Bosche et al and the accompanying editorial comment in the last issue of Stroke.1 The authors should be commended on their elegant work with multi-modality monitoring in predicting "malignant" infarction with large middle cerebral artery ischemia. However, the technique of in vivo cerebral microdialysis utilized in this study deserves several comments that are generally applicable to similar studies.

In vivo cerebral microdialysis is a powerful research technique that has been rapidly adapted in clinical and experimental neurosciences for purposes of analyzing neurochemical dynamics of brain injury. This has resulted in abundant literature from studies in carefully controlled animal models that quantitates neurochemical changes in focal cerebral ishemia. Over the last few years, extension of laboratory-based studies have been reported2–5 in patients with large hemispheric infarctions, traumatic brain injury,6 global cerebral ischemia7 and subarachnoid hemorrhage8,9. Neuroprotective strategies,10 including hypothermia,11–13 and their effects on neurotransmitter release have been well-described using this technique. However, this technique has significant limitations for facilitating new discoveries in the clinical setting that include (a) small sampling volume of brain tissue around the microdialysis probe (at best, a radial distance of a few millimeters around the probe); (b) poor time resolution (collection time of 120 minutes in the study by Bosche et al); (c) the presence of reactive gliosis around the probe with chronic indwelling probes, with subsequent poor recovery of the molecules of interest; (d) a wide intersubject variability in basal neurochemical values and following tissue perturbations; and (e) difficulties in data interpretation as a consequence of tissue trauma following probe placement. Further, large dialysate volumes are often required to optimize neurochemical recovery when slow flow rates of perfusate are used. In the study by Bosche et al, probe positions were accurately localized in relation to infarcted tissue by utilizing CT scan, a confirmation that is frequently lacking in other reports. While some experimental studies have suggested14 that neuropathological changes that occur around the catheter following prolonged (up to 7 days) microdialysis probe placement should not interfere with local brain metabolism, controversy remains concerning this issue.

In addition, a number of issues arise pertaining to data presentation when utilizing microdialysate measurements. First, data generated from microdialysis can be voluminous and many studies present results at selected or "time-averaged values." One of the distinct advantages of the technique is the ability to follow changes over time. These repeated measurements can be correlated with pathophysiological systemic processes as well as local neurochemical derangements in the injured brain. Thus, it is extremely important to examine individual sample values before subjecting them to averaging and statistical analysis. Second, the data are frequently presented as "trends" of neurochemical change or percentage change from baseline values, in part because of the large sample variability within treatment groups. Furthermore, baseline neurochemical values reported in most studies are from an anatomical area of brain that is already "injured," and comparison sampling from a distant site or contralateral "uninjured" area is lacking. Third, most studies perform dialysate collections over 60 to 120 minutes and report them as such. However, such time periods are too long if one wishes to initiate therapeutic maneuvers to ameliorate secondary brain injury. Consequently, the majority of reports that utilize microdialysis in clinical paradigms provide data that describes "phenomenology" on injury (eg, excitatory amino acid release in ischemic brain tissue and amelioration with therapeutic maneuver, such as hypothermia11–13). Unfortunately, this descriptive approach provides limited new information and can be repetitious of other published work.

As noted in the accompanying editorial comment, the study by Bosche et al provides newer insights into regional neurochemistry underlying "malignant" cerebral infarction. However, these results must be validated by other investigators. Furthermore, newer methods must be developed that circumvent current important limitations, including time resolution of regional microchemistry, and that will allow reasonable study of the effect of therapeutic intervention, not just the disease course. Recent technological advances, comprising continuous neuromonitoring15 of parameters such as brain oxygen, CO2, pH, and temperature and "online" display of relative changes, in conjunction with local neurochemical measures, could prove to be invaluable in the future care of critically ill stroke patients.

References

  1. Bosche B, Dohmen C, Graf R, Neveling M, Staub F, Kracht L, Sobesky J, Lehnhardt FG, Heiss WD. Extracellular concentrations of non-transmitter amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke. 2003; 34: 2908–2913.[Abstract/Free Full Text]
  2. Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke. 2002; 33: 519–524.[Abstract/Free Full Text]
  3. Schabitz WR, Berger C, Schellinger PD, Aschoff A, Steiner T, Schwab S. Neurometabolic changes during treatment with moderate hypothermia in a patient suffering from severe middle cerebral artery infarction. Cerebrovasc Dis. 2001; 12: 298–302.[CrossRef][Medline] [Order article via Infotrieve]
  4. Berger C, Annecke A, Aschoff A, Spranger M, Schwab S. Neurochemical monitoring of fatal middle cerebral artery infarctions. Stroke. 1999; 30: 460–463.[Abstract/Free Full Text]
  5. Schnewes S, Grond M, Staub F, Brinker G, Neveling M, Dohmen C, Graf R, Heiss WD. Predictive value of neurochemical monitoring in large middle cerebral artery infarction. Stroke. 2001; 32: 1863–1867.[Abstract/Free Full Text]
  6. Yamaguchi S, Nakahara K, Miyagi T, Tukotomi T, Shigemori M. Neurochemical monitoring in the management of severe head-injured patients with hypothermia. Neural Res. 2000; 22: 657–664.
  7. Nakashima K, Todd MM. Effect of hypothermia on rate of excitatory amino acid release after ischemic depolarization. Stroke. 1996; 27: 913–918.[Abstract/Free Full Text]
  8. Nilsson OG, Brandt L, Ungerstedt U, Saveland H. Bedside detection of brain ischemia using intracerebral microdialysis: subarachnoid hemorrhage and delayed ischemic deterioration. Neurosurgery. 1999; 45: 1176–l184.[CrossRef][Medline] [Order article via Infotrieve]
  9. Staub F, Graf R, Gabel P, Kochling M, Klug N, Heiss WD. Multiple interstitial substances measured by microdialysis in patients with subaracbnoid hemorrhage. Neurosurgery. 2000; 47: 1106–1115.[CrossRef][Medline] [Order article via Infotrieve]
  10. Koinig H, Vornik V, Rueda C, Zornow MH. Lubeluzole inhibits accumulation of extracellular glutamate in the hippocampus during transient global cerebral ischemia. Brain Res. 2001; 898: 297–302.[Medline] [Order article via Infotrieve]
  11. Huang FP, Zhou LF, Yang GY. Effects of mild hypothermia on the release of regional glutamate and glycine during extended transient focal cerebral ischemia in rats. Neurochem Res. 1998; 23: 991–996.[CrossRef][Medline] [Order article via Infotrieve]
  12. Mori K, Maeda M, Miyazaki M, Iwase H. Effect of mild (33°C) and moderate (29°C) hypothermia on cerebral blood flow and metabolism, lactate, and extracellular glutamate in experimental head injury. Neurol Res. 1998; 20: 719–726.[Medline] [Order article via Infotrieve]
  13. Lo EH, Steinberg GK, Panahian N, Maidment NT, Newcomb R. Profiles of extracellular amino acid changes in focal cerebral ischemia: effects of mild hypothermia. Neurol Res. 1993; 15: 281–287.[Medline] [Order article via Infotrieve]
  14. Whittle IR, Glasby M, Lammie A, Bell H, Ungerstedt U. Neuropathological findings after intracerebral implanation of microdialysis catheter. Neuroreport. 1998; 24: 2821–2825.
  15. Zauner A, Doppenberg E, Soukup J, Menzel M, Young HF, Bullock R. Extended neuromonitoring: new therapeutic opportunities? Neurol Res. 1998; 20 (suppl 1): S85–90.[Medline] [Order article via Infotrieve]

Cerebral Microdialysis in Stroke Patients: Potentials and Limitations of a Method with Longitudinal Information

Response

Bert Bosche, MD; Christian Dohmen, MD Rudolf Graf, PhD

Klinik und Poliklinik für Neurologieder Universität zu Köln

We have to thank Dr. Bhardwaj for his valuable comments on our microdialysis study on patients suffering from hemispheric stroke,1 and we would like to briefly respond. Cerebral in vivo microdialysis has become a common research technique in neuro critical care in recent years,2–5 and one example is monitoring in severe stroke patients to predict and evaluate the further clinical course.6,7

Indeed, in vivo microdialysis has limitations in our study as well as in general. First, the information on neurochemical substances in the extracellular fluid originates from a small tissue volume and deductive conclusions about the metabolic state of larger brain regions cannot be drawn. Second, the time resolution (sampling time) of cerebral microdialysis in our study was 120 minutes. The method, however, allows higher time resolution8,9 or even continuous measurement.10 In our study, we used microdialysis to get information over an 80-hour time period, in which malignant brain edema develops.11 At this stage of an ongoing study, we were searching for neurochemical predictors of malignant MCA infarction. Hence, the analysis of a wide spectrum of substances seemed more important to us rather than to maximize the time resolution. The next step would include improvement of time resolution and we are currently discussing whether nontransmitter amino acids are suitable for this purpose. Third, the presence of reactive gliosis around the microdialysis catheter influences the recovery of substances through the microdialysis membrane, but it is common sense that this gliosis plays a minor role in the first hours after implantation.12–15 To predict malignant MCA infarction, we used dialysate from the first 12 hours measurement. During this time period, recovery remains stable in animal experiments, and even over a time period of 80 hours, tissue alterations like gliosis and/or hematoma are not prominent in the surrounding of the catheter.14 Fourth, the inter-subject variability in basal neurochemical values and the lack of reference values taken, for example, from the contralateral hemisphere as described by other authors16 is a fundamental problem of our and of other microdialysis studies in humans. But ethical aspects make investigations of basal or reference values delicate or impossible. Finally, variable tissue trauma following probe implantation is also a problem that influences the microdialysis data. Standardized implantations as performed in our study may lower this source of error but cannot eliminate it. However, several experimental studies17–20 have shown that extracellular amino acid and other substance concentrations normalized less than 2 hours after implantation trauma by microdialysis probe.

Finally, we agree with Dr. Bhardwaj and would like to underscore the need to supplement microdialysis with other techniques to overcome limitations of individual methods as shown by other authors.21 In our group we combine multimodal neuromonitoring comprising measurements of ICP, brain tissue oxygen, and cerebral microdialysis with PET22 and currently MRI. However, it seems important to point out again that longitudinal information obtained by multimodal neuromonitoring is essential for understanding dynamics of pathophysiological alteration in brain tissue. This is the crucial advantage over neuroimaging. CT, MRI, or PET provide only snapshot-like information about brain tissue, since sequential imaging of critically ill patients is a medical and logistical problem. Further studies with the combination of imaging and multimodal neuromonitoring are needed to better understand the pathophysiology of hemispheric infarction that may lead to new therapeutic strategies. Known strategies like hemicraniectomy23 should be evaluated with both invasive and noninvasive approaches.

References

  1. Bosche B, Dohmen C, Graf R, Neveling M, Staub F, Kracht L, Sobesky J, Lehnhardt FG, Heiss WD. Extracellular concentrations of non-transmitter amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke. 2003; 34: 2908–2913.[Abstract/Free Full Text]
  2. Persson L, Hillered L. Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg. 1992; 76: 72–80.[Medline] [Order article via Infotrieve]
  3. Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP. Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab. 1992; 12: 12–24.[Medline] [Order article via Infotrieve]
  4. Hutchinson PJ, Gupta AK, Fryer TF, Al-Rawi PG, Chatfield DA, Coles JP, O’Connell MT, Kett-White R, Minhas PS, Aigbirhio FI, Clark JC, Kirkpatrick PJ, Menon DK, Pickard JD. Online monitoring of substrate delivery and brain metabolism in head injury. Acta Neurochir Suppl. 2000; 76: 431–435.
  5. Staub F, Graf R, Gabel P, Kochling M, Klug N, Heiss WD. Multiple interstitial substances measured by microdialysis in patients with subarachnoid hemorrhage. Neurosurgery. 2000; 47: 1106–1115.[CrossRef][Medline] [Order article via Infotrieve]
  6. Berger C, Annecke A, Aschoff A, Spranger M, Schwab S. Neurochemical monitoring of fatal middle cerebral artery infarction. Stroke. 1999; 30: 460–463.[Abstract/Free Full Text]
  7. Schneweis S, Grond M, Staub F, Brinker G, Neveling M, Dohmen C, Graf R, Heiss WD. Predictive value of neurochemical monitoring in large middle cerebral artery infarction. Stroke. 2001; 32: 1863–1867.[Abstract/Free Full Text]
  8. Cheng FC, Yang DY, Wu TF, Chen SH. Rapid online microdialysis hyphenated technique for the dynamic monitoring of extracellular pyruvate, lactic acid and ascorbic acid during cerebral ischemia. J Chromatogr B Biomed Sci Appl. 1999; 723: 31–38.[Medline] [Order article via Infotrieve]
  9. Feuerstein TH, Langemann H, Gratzl O, Mendelowitsch A. A four lumen screwing device for multiparametric brain monitoring. Acta Neurochir (Wien). 2000; 142: 909–912.[CrossRef][Medline] [Order article via Infotrieve]
  10. Hopwood SE, Boutelle MG, Parkin MC, Bezzina EL. Strong AJ. Rapid sampling of glucose and lactate using online microdialysis in a model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2003; 23 (suppl): 115.
  11. Rosenberg GA. Ischemic brain edema. Prog Cardiovasc Dis. 1999; 42: 209–216.[CrossRef][Medline] [Order article via Infotrieve]
  12. Benveniste H, Drejer J, Schousboe A, Diemer NH. Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J Neurochem. 1987; 49: 729–734.[Medline] [Order article via Infotrieve]
  13. Benveniste H, Diemer NH. Cellular reactions to implantation of a microdialysis tube in the rat hippocampus. Acta Neuropathol (Berl). 1987; 74: 234–238.[CrossRef][Medline] [Order article via Infotrieve]
  14. Shuaib A, Xu K, Crain B, Siren AL, Feuerstein G, Hallenbeck J, Davis JN. Assessment of damage from implantation of microdialysis probes in the rat hippocampus with silver degeneration staining. Neurosci Lett. May; 112: 149–154.
  15. Whittle IR, Glasby M, Lammie A, Bell H, Ungerstedt U. Neuropathological findings after intracerebral implantation of microdialysis catheters. Neuroreport. Aug; 9: 2821–2825.
  16. Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke. Feb; 33: 519–524.
  17. Zetterstrom T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB. Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett. 1982; 29: 111–115.[CrossRef][Medline] [Order article via Infotrieve]
  18. Van Wylen DG, Park TS, Rubio R, Berne RM. Increases in cerebral interstitial fluid adenosine concentration during hypoxia, local potassium infusion, and ischemia. J Cereb Blood Flow Metab. Oct; 6: 522–528.
  19. Morimoto K, Shimizu H, Hayakawa T, Shimada N, Nii Y, Masana Y, Kato A, Mogami H. Purine catabolites in cerebral interstitial fluid during progression of and recovery from ischemia. Neurol Med Chir (Tokyo). 1991; 31: 129–134.[Medline] [Order article via Infotrieve]
  20. Matsumoto K, Graf R, Rosner G, Taguchi J, Heiss WD. Elevation of neuroactive substances in the cortex of cats during prolonged focal ischemia. J Cereb Blood Flow Metab. 1993; 13: 586–594.[Medline] [Order article via Infotrieve]
  21. Zauner A, Doppenberg E, Soukup J, Menzel M, Young HF, Bullock R. Extended neuromonitoring: new therapeutic opportunities? Neurol Res. 1998; 20 (suppl 1): S85–S90.[Medline] [Order article via Infotrieve]
  22. Dohmen C, Bosche B, Graf R, Staub F, Kracht L, Sobesky J, Neveling M, Brinker G, Heiss WD. Prediction of malignant course in MCA infarction by PET and microdialysis. Stroke. 2003; 34: 2152–2158.[Abstract/Free Full Text]
  23. Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, Hacke W. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke. 1998; 29: 1888–1893.[Abstract/Free Full Text]




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