ORIGINAL ARTICLE

Assessment of physiological parameters within glioblastomasin awake patients: a prospective clinical study

IAN R. WHITTLE, NEO STAVRINOS, HAZEM AKIL, YH YAU & STEPHANIE C. LEWIS

Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU

AbstractObject. Multiparametric brain monitoring probes now make it possible to measure cerebral physiology. This prospectiveclinical study was designed to evaluate the pathophysiological environment of tumoural and peritumoural tissue O2, CO2,pH, HCO3- and temperature of awake patients with glioblastoma.Methods. A Neurotrend multiparametric sensor was placed using intraoperative image guidance into glioblastoma afterbiopsy under general anesthetic. Postoperative monitoring was then performed in awake patients.Results. Twelve patients were recruited and monitoring was performed, and well tolerated in 9 for up to 22 hrs. Meanglioblastoma tumour values were: tissue oxygen pressure (PtiO2) 21.0 mmHg, standard deviation+ 7.9; PtiCO2 60.2+ 17.2mmHg; temperature 36.9+ 0.48C, pH 7.08 þ 0.2; and HCO3 17.1+ 3.7. Mean peritumoural brain values in 5 patientswere PtiO2 29.1+ 27.6 mmHg; PtiCO2 48.6+ 7.0 mmg; temperature 36.4+ 0.68C; pH 7.20+ 0.09 and HCO3

19.1+ 3.5. There were trends for the PtiO2 to decrease with increasing brain depth. As glioblastoma PtiCO2 levelsdecreased, pH increased. There were no relationships between either tumoural PtiO2 and pH, or PtiO2 and PtiCO2, howeverthere were large intra- and inter-tumoural variation in monitoring values. There were technical problems in some patientswith the Neurotrend sensor that limited its application, and that compromised aspects of data collection and interpretation,particularly of PtiO2.Conclusion. This study has shown that this novel approach to monitoring glioma pathophysiology is feasible and welltolerated by patients. The data, much of which is novel, contributes to the knowledge of glioblastoma pathophysiology.However, further study and clinical exploitation awaits the development of a more reliable multiparametric sensor.

Key words: glioblastoma, monitoring, oxygen, hypoxia pathophysiology.

Introduction

The metabolic microenvironment within glioblasto-

ma and peri-tumoural brain tissue will influence

tumour proliferation, ischemic cell death and apop-

tosis.1,2,3 There is substantial direct and indirect

evidence that glioblastomas have foci of profoundly

hypoxic tissue.1–4 In glioblastoma hypoxia-related

genes comprise a large subset of consistently

upregulated genes,4 Hypoxia Inducible Factor 1

alpha is expressed in the nuclei of pseudopallisad-

ing,2,3 and vascular endothelial hyperplasia arises in

response to angiogenic factors secreted by hypoxic

cells.3 Direct data from intraoperative recordings

under general anaesthetic shows that the interstitium

of glioblastomas, and peritumoural brain have foci of

profoundly hypoxic tissue.5,6 However, the type of

anaesthesia is important, since in a series of cases that

employed either general or local anaesthetic, there

were significantly lower tumoural and peritumoural

PtiO2s with general, compared to local, anaesthesia.5

Additionally high resolution measurements of

tumoural pH and PO2 in experimental tumours have

shown considerable heterogeneity of findings.7 Evans

and colleagues,8 using both EF5 binding and

intraoperative measurements with Eppendorf polaro-

graphic electrodes, have suggested that most malig-

nant gliomas either had near normal PtiO2 or were

only mildly hypoxic. Semiquantitaive patterns of

nitroimidazole binding have confirmed these findings

experimentally,9 and in humans with either PET10 or

radioisotopes.11

There remains considerable debate therefore about

the physiology of the interstitium of malignant

gliomas since findings are critically dependent on

technique and methodology. Ideally in vivo quanti-

tative measurements of glioblastoma tissue physiolo-

gical environment should be obtained in awake

Correspondence: Dr. I. R. Whittle, Dept. Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU. Tel.: 0131 537 2103. Fax: 0131 357 25614.

E-mail: ian.whittle@ed.ac.uk

This work was presented in part as at the European Congress of Neuro-oncology, Vienna, September 2006, and the British Neurosurgical Research Society,

Manchester, April, 2007.

Received for publication 24 December 2009. Accepted 2 March 2010.

British Journal of Neurosurgery, August 2010; 24(4): 447–453

ISSN 0268-8697 print/ISSN 1360-046X online ª The Neurosurgical Foundation

DOI: 10.3109/02688691003746290

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patients and record multiple parameters simulta-

neously over a lengthy time period. Such a scenerio

was deemed ‘impossible’;5 however, Beppu and

colleagues12 showed the feasibility of long-term

PtiO2 monitoring in patients with malignant glioma.

The advent of intracranial multiparametric mon-

itoring probes, has lead to their wide application

within the neurointensive care setting in neurosurgi-

cal patients with drug-induced coma following either

head injury or subarachnoid haemorrhage.13–15 One

study, not dissimilar to ours in design, also used a

multiparametric probe for intraoperative monitoring

of the effects of dural opening and brain tumour

excision.16 Our study was therefore designed to

assess simultaneously levels of PtiO2, PtiCO2, pH,

HCO3- and temperature using direct recordings

from a single multisensing probe (Neurotrend,

Codman, Raynham, MA) inserted into a glioblasto-

ma after imaged guided burr-hole biopsy. Although

the Neurotrend monitor has been used following

neurotrauma and various types of stroke, this study is

the first to use it to investigate aspects of brain

tumour interstitial biology. This study aimed to

evaluate 3 questions: (1) the feasibility of the

technique and any problems associated with it; (2)

to document multi-parametric metabolic profiles in

glioblastoma; and, (3) to compare these data with

previously obtained results.

Methods

Patients who were to undergo image guided burr-

hole brain tumour biopsy, since the tumours were

either not resectable or there were clinical contra-

indications to resection, and whose neuroradiology

suggested a malignant glioma were recruited for the

study. Fully informed written, consent was obtained.

The study was approved by the regional ethics

committee (LREC/2003/1/5).

The Neurotrend monitor was calibrated at the

time of induction of general anaesthetic. Either after

completion of the tumour biopsy, or whilst awaiting

confirmation of a positive smear on frozen section, a

twist drill burr-hole was placed adjacent to the

burrhole used for the biopsy. The trajectory of the

twist drill burrhole was chosen using the BrainLab

(BrainLab, Munich) image guidance biopsy system

so that the tip of the Neurotrend multiparameter

sensor could be placed deep to the central part of the

tumour interstitium (Figure 1). A Codman Bolt

FIG. 1. Two Intraoperative screen saver shots that demonstrates the technique of Image Guided insertion of the Neurotrend probe into the

tumour. The general direction of the trajectory can be imaged, a twist drill made and Codman bolt inserted. The BrainLAB guide tool can

then be placed in the Codman bolt, a virtually reality extension added to determine desired depth of insertion (red). The Neurotrend is then

inserted. Its rigid central stylette means that it should pass straight along the imaged trajectory. Both images show that the monitoring device

is going to lie within and traverse quite heterogenous tumoural and peritumoural tissue. The volume averaging that is inherent in the

measuring technique of the Neurotrend parameters could well mask significant focal regional variations in the various parameters.

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(Codman) was then placed into the twist drill hole in

the skull, the BrainLab guidance tool was then placed

down the Bolt to confirm placement of the Neuro-

trend probe in the tumour interstitium using the

virtual reality extension tool of the Brain Lab system

and to obtain an insertion depth for the probe tip

(Figure 1). The Neurotrend monitor probe was

adjusted to desired insertion length, then placed into

the Bolt, the introducing stylette withdrawn and Luer

lock system tightened (The metal stylette down the

centre of the probe made it ideal for insertion into

tumour tissue using image guidance and a locking

bolt because it was rigid, straight and it should limit

bending as it was inserted into the brain). A screen-

saver photo-image was then taken and saved to a zip-

drive (Figure 1). After completion of insertion the

patient was then extubated, recovered and returned

to the ward. For the first 4 hours postoperatively,

most patients were given supplemental oxygen

(100%, 5 L/min) by nasal prongs. Peripheral tissue

Oxygen saturation was monitored using a digital

sensor.

The patient data module was then connected

(about 2 hours after insertion of the Neurotrend)

and data (O2, CO2, pH, temperature and HCO3-)

recorded every 30 seconds directly through a RS232

connection to a laptop using the Hyperterminal

program. The patient was able to sit up, converse,

eat, drink and sleep during an overnight period of

recording. After intervals of 2–5 hours, the Neuro-

trend monitor was withdrawn from the brain

approximately 5 mm to enable multifocal tumoural

sampling. Within 24 hrs of surgery the Neurotrend

monitor was removed and the Bolt unscrewed from

the cranium. One or two sutures placed around the

bolt insertion site, at the time of operation, were then

tied to oppose the scalp edges. The data was then

transferred to an excel spread sheet and analysed.

Results

Twelve patients were recruited to the study. Place-

ment of the additional twist drill hole, locking bolt

and probe took between 10–15 minutes and targeting

was easy using image guidance. Data was obtained

from 9 patients since the Neurotrend calibration

system failed on 2 occasions, and in one patient the

lesion was too small and deep to be certain that the

Neurotrend tip could be placed reliably into the

tumour. There were no complications of monitoring,

and no patient voiced concern during or on removal

of the monitor. All monitored patients had confirmed

histological diagnosis of Glioblastoma Multiforme

(WHO IV).

Periods of monitoring ranged from 3 to 22 hours

(median 12 hours). During this time patient oxygen

saturation was with a few exceptions, for very brief

periods, 496%. The shortest period of monitoring

(3 hrs) occurred because the Luer lock connecting

the Neurotrend monitor to the skull bolt loosened

with partial distraction of monitor from the brain.

This problem also occurred in 2 other patients (after

6 hours and 10 hours of monitoring). The O2 sensor

failed to work in 1 patient after 15 minutes, and

another after 6 hours. In the latter patient, the sensor

malfunction occurred after the monitor had been

withdrawn 10 mm within the tumour interstitium. In

2 patients there were fluctuating PtiO2 readings

down to zero after withdrawal of the monitor through

the tumour into peritumoural brain (vide infra), but

in both patients readings later stabilised. The CO2

sensor malfunctioned shortly after recordings began

in 1 patient.

Good quality data (Figure 2) was obtained from 37

regions (24 tumoural and 13 peritumoural) regions

with a median 3 monitoring regions per patient (range

1–12). Depth of monitoring ranged from 7 cm to

2.5 cm below dura. The overall tumoural mean PtiO2

level across patients (n¼ 9) was 21.0 mmHg (+stan-

dard deviation 7.9), and the within patient mean

ranged from 9.8+ 2.2 to 33.5+ 2.1. The overall

peritumoural mean PtiO2 level across patients (n¼ 5)

was 29.1+ 27.6 mmHg, and the within patient mean

ranged from 3.3+ 2.4 to 58.3+ 6.0 mmHg. The

wide range of values recorded a can be seen in Table I

and Figure 3. The difference between peritumoural

and tumour PtiO2 was not statistically significant

(mean difference peritumoural brain 8.1+ 28.8

mmHg higher than tumour (n¼ 5; p¼ 0.58). In 2

patients mean peritumoural PtiO2 was measured at

3.3 and 3.2 mmHg, which is highly suggestive of

monitor O2 sensor malfunction. There was a trend

that as depth of the probe in the brain increased,

tumour tissue PtiO2 levels decreased, from average 33

mmHg at 3 cm to 13 mmHg at 6 cm. This effect was

also seen in normal brain.

The overall mean brain tumour PtiCO2 level

across patients was 60.2+ 17.5 mmHg, and the

within patient mean ranged from 46.1+ 0.6 mmHg

to 102.4+ 11.5 mmHg. The overall mean peritu-

moural PtiCO2 across patients was 48.6+ 7.0

mmHg (range from 41.0+ 9.1 mmHg to

57.0+ 4.0 mmHg). The difference between mean

peritumoural brain and tumour PtiCO2 (11.7 mmHg

higher in tumour) was not statistically significant

(n¼ 5; p¼ 0.24). Brain tumour tissue PtiCO2 did

not show a trend with different depths of monitoring.

The overall mean brain tumour pH across patients

was 7.08+ 0.2 (range from 6.81+ 0.05 to

7.28+ 0.01). Mean peritumoural brain pH was

7.20 (+0.1) and range from 7.12 (+.0.02) to

7.34+ 0.01. The difference between peritumoural

and tumour pH was not statistically significant (mean

difference¼ 0.12+ 0.1 higher in peritumoural tissue;

n¼ 5; p¼ 0.45). The pH did not show a trend

between monitoring depth and pH. As glioma

PtiCO2 levels decreased, pH increased, as expected

(Figures 2,3). However, there were no relationships

between either tumoural PtiO2 and pH, or PtiO2 and

PtiCO2.

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The overall mean brain tumour HCO3 level across

patients was 17.1+ 3.7, range from 10.4+ 0.7 to

21.3+ 0.12. The mean peritumoural HCO3 level

across patients was 19.1+ 3.5) and range from

16.0+ 0.7 to 23.3+ 6.2. The difference between

peritumour and tumour HCO3 of 2.0+ 4.65, higher

in peritumoural brain, was not statistically significant

(n¼ 5). The HCO3 did not show any trend related to

different depths of monitoring.

The overall mean brain tumour temperature across

patients was 36.9+ 0.48C (range from 36.6+ 0.28C.

to 37.4+ 0.18C). The overall mean peritumoural

temperature across patients was 36.4+ 0.68C, and

range from 35.8+ 0.68C to 36.9+ 0.18C. The

temperature increased slightly at greater depths,

from 36.5 at 3 cm to 37.0 at 6 cm. Temperature

was higher in tumour than peritumoural brain (mean

difference¼ 0.5+ 0.58C) but this was not statisti-

cally significant (n¼ 5; p¼ 0.07) and probably

occurred because the peritumoural brain was more

superficial than tumour.

Discussion

This study has shown that the technique of post-

operative multiparametric monitoring of the glioma

physiological environment is feasible using place-

ment of a probe positioned using intraoperative

image guidance. Placement of the additional twist

drill hole, locking bolt and probe was relatively easy

using image guidance and performed whilst awaiting

a frozen section smear, thus not prolonging the

operation time. Post operatively the monitoring was

readily tolerated for up to 22 hours, and the probe

could be removed with minimal discomfort. These

findings, which are similar to those of Beppu and

colleagues,12 who stereotactically placed a Clark O2

monitoring electrode into tumoural and peritumour-

al brain. Together, these studies suggest in vivo

physiological studies of glioma biology can be done

in the postoperative period using invasive monitoring

with low morbidity and minimal patient discomfort.

The Neurotrend monitor used in this study was,

however, unreliable. Failures of calibration, problems

with oxygen measurement failure either ab initio or

during a period of monitoring have previously been

documented.16–18 Such unreliability makes interpre-

tation of PtiO2 data somewhat difficult, since it was

difficult to know in some cases whether the zero or

near zero recording was genuine or artifactual in

origin. In addition several zero PtiO2 recordings

occurred after withdrawal of the Neurotrend probe

small distances through the glioma, suggesting the

probe is sensitive to mechanical distortion.

Nonetheless, the study does contribute further to

understanding of metabolic parameters in malignant

glioma. Many of the individual tumoural PtiO2

measurements in our study are similar to readings

obtained from intraoperative studies using polaro-

graphic electrodes. However our mean value of 21

mmHg is higher than the mean malignant glioma

PtiO2 of Collingridge et al.5 (5.6 mmHg, n¼ 10),

Rampling et al.19 (7.4 mmHg, n¼ 15), Clavo et al.20

(13.2 mmHg: n¼ 3), Kayama et al.21 (16.6 mmHg,

FIG. 2. A series of graphs showing monitoring values for

Glioblastoma tissue oxygen, carbon dioxide, pH and bicarbonate

levels (patient 3). In this patient all the parameters remain relatively

stable irrespective of location. When the monitor is withdrawn from

the brain (red lines) all values change as expected, e.g., temperature

and CO2 fall, and oxygen rises. The different coloured lines

represent monitoring from 4 different sites within the tumour as the

probe is withdrawn (i.e., tumour1, tumour 2, etc). Time 0

represents the start of monitoring at each these specific sites.

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n¼ 6), Beppu et al.12 (mean 9.2 to 11.2 mmHg,

n¼ 16) and Evans et al.8 415 mmHg, n¼ 5. All

these values are however greater than the 1.5 mmHg

required to maintain neuronal mitochondrial aerobic

metabolism.19

Variability in results arise because of differences in

tumour depth recording, tumoural histopathological

heterogeneity (see Figure 1), use of sedation versus

general anesthetic, the regional interstitial variabilityTA

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FIG. 3. A series of graphs showing monitoring values for

Glioblastoma tissue oxygen, CO2, pH and HCO3 levels (patient

5). In this patient there is considerable variability in some

parameter readings, particularly the O2 and HCO3 (cf. Fig. 2).

The O2 recordings are relatively stable over the initial 5 tumoural

sites (i.e., tumour 1–5). Thereafter there is instability of the

peritumoural O2 recordings with wide fluctuations in values that

are not mirrored in any other parameters (i.e., Peritumour 1-7).

The different coloured lines represent monitoring from 12

different sites within the tumour. Time 0 represents the start of

monitoring at each of these specific sites.

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in PtiO2 values7 and differences in monitoring

technique. PtiO2 is higher in malignant gliomas

where measurements were performed using awake

techniques rather than general anaesthesia.5,12 Brain

PtiO2 levels are also to some degree depth sensitive

ranging from 23.8+ 8 mmHg at depths of 22-

27 mm below dura to 33.3+ 13 mmHg at 7–

12 mm below the dura.13 A similar pattern of both

decreasing brain PtiO2 with depth and brain PtiO2

were found in this study.

Polarographic methods also provide more focal

tissue recordings, whereas the Neurotrend O2 sen-

sing probe volume averages values over a 10–15 mm

long region. The Clarke monitoring electrode used

by Beppu and colleagues12 recorded over a 10 mm

distance and the Licox has a O2 sensitive surface of

7.1 mm2.13 These differences in PtiO2 volumetric

sampling together with tissue heterogeneity in

gliobastoma may well explain the apparently contra-

dictory findings from different studies.4,7,8 The

heterogeneity of PtiO2 findings within glioblastoma

may also explain the failure of hypoxic-radiosensiti-

zers to improve outcome in randomised controlled

clinical trials.22

Mean PtiO2 measurements recorded in peritu-

moural white matter during operations include

means of 50.5 mmHg21, 7–16 mmHg,16 10.2

mmHg6, and 5.9 mmHg under general anaesthesia

and 11.1 mmHg under local anaesthesia.5 These

values are, with the 1 exception, again lower than the

peritumoural brain PtiO2 levels in this study (mean

29 mmHg), and also lower than those recorded by

Beppu and colleagues12 in the only other study

recording awake patients with glioblastoma (mean

17.9 mmHg). Methodological reasons may explain

much of these differences. Nonetheless, the values

for our study are higher than the critical threshold for

hypoxic injury (15–20 mmHg),15 those recorded in

brain following either spontaneous SAH or traumatic

brain injury (means 20.9 mmHg3 and 11–15

mmHg17). The relatively high values in our study

are a little surprising given that the Neurotrend

monitor may underestimate brain PtiO2 compared

with the commonly used Licox probe3,17 (e.g., Licox

27.7 mmHg v Neurotrend 20.9 mmHg).

With regard to the other parameters Pennings and

colleagues16 recorded peritumoural brain mean

PtiCO2 values of 48+ 7 mmHg under general

anesthetic, which is identical to the values recorded

in our study. They did not publish their pH,

temperature and HCO3 findings. Zauner and collea-

gues14 state that a PtiCO2 of 55 mmHg is ‘normal’,

and that brain pH is inversely related to PtiCO2, as

was found in this study. Their mean temperature

value of 36.68C was almost identical to that recorded

in this study, as was their mean pH.14

The data presented here for GBM PtiCO2,

temperature, pH and HCO3- is to the best of our

knowledge novel. Despite the unreliability of the O2

sensor, and the fact that it ‘volume averages’ PtiO2,

the multiparametric findings have confirmed con-

ventionally accepted trends about the pathophysio-

logical environment of glioblastomas compared to

normal brain, viz. they have lower pH, HCO3 and

oxygen levels and higher pH. The potential utility of

this novel in vivo clinical experimental approach to

glioma biology will unfortunately have to await

development of more robust monitoring probes.

However, the study has shown the feasibility and

patient acceptance of this approach.

Acknowledgment

This work was funded by a research grant from the

Melville Trust.

Declaration of interest: IRW received an Educa-

tional Travel Grant from Codman to attend a

conference on Neuromonitoring in June 2005. IRW

has also been paid consultancy and received ad hoc

lecture fees from Link Pharmaceutical, Archimedes

Pharmaceutical, Schering-Plough and Ark Thera-

peutics. No other authors have any conflict of

interest. The authors alone are responsible for the

content and writing of the paper.

References

1 Brat DJ, Castellano-Sanchez AA, et al. Pseudopalisades in

glioblastoma are hypoxic, express extracellular matrix pro-

teases, and are formed by an actively migrating cell population.

Cancer Res 2004 Feb 1;64(3):920–927.

2 Evans SM, Judy KD, Dunphy I, et al. Hypoxia is important in

the biology and aggression of human glial brain tumours. Clin

Cancer Res 2004;10:8177–8184.

3 Rong Y, Durden DL, Van Meir EG, Brat DJ. ‘Pseudopalisad-

ing’ necrosis in glioblastoma: a familiar morphologic feature

that links vascular pathology, hypoxia, and angiogenesis.

J Neuropathol Exp Neurol 2006;65(6):529–539.

4 Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD,

Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown

PO, Israel MA. Gene expression profiling reveals molecularly

and clinically distinct subtypes of glioblastoma multiforme.

Proc Natl Acad Sci 2005;102:5814–5819.

5 Collingridge DR, Piepmeier JM, Rockwell S, Knisely JPS.

Polarographic measurements of oxygen tension in human

glioma and surrounding peritumoural brain tissue. Radiother

Oncol 1999:53:127–131.

6 Cruikshank GS, Rampling R. Peri-tumoural hypoxia in human

brain: preoperative measurement of the tissue oxygen tension

around malignant brain tumours. Acta Neurochir Suppl (Wien)

1994;60:375–377.

7 Helminger G, Yuan F, Dellian M, Jain RK. Interstitial pH and

PO2 gradients in solid tumours in vivo: High-resolution

measurements reveal a lack of correlation. Nat Med 1997;

3;177–182.

8 Evans SM, Judy KD, Dunphy I, et al. Comparative measure-

ments of hypoxia in human brain tumours using needle

electrodes and EF5 binding. Cancer Res 2004;64:1886–

1892.

9 Parliament MB, Franko AJ, Allalunis A, et al. Anomalous

patterns of nitroimidazole binding adjacent to necrosis in

human glioma xenografts: possible role of decreased oxygen

consumption. Br J Cancer 1997;75:311–318.

10 Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF.

Hypoxia in human gliomas: demonstration by PET with

Fluormisonidazole. J Nucl Med 1992;33(12):2133–2137.

452 I. R. Whittle et al.

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ded

from

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.com

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For

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11 Groshar D, McEwan AJ, Parliament MB, et al. Imaging

tumor hypoxia and tumor perfusion. J Nucl Med 1993;

34(6):885–888.

12 Beppu T, Kamada K, Yoshida Y, Arai H, Ogasawara K,

Ogawa A. Change of oxygen pressure in glioblastoma tissue

under various conditions. J Neurooncol 2002;58(1):47–52.

13 Dings J, Meixensberger J, Jager A, Roosen K. Clinical

experience with 118 brain tissue oxygen partial pressure

catheter probes. Neurosurgery 1998;43(5):1082–1095.

14 Zauner A, Daugherty WP, Bullock MR, Warner DS. Brain

oxygenation and energy metabolism: part 1–Biological function

and pathophysiology. Neurosurgery 2002;51(2):289–302.

15 Zauner A, Doppenberg E, Woodward JJ, et al. Multiparametric

continuous monitoring of brain metabolism and substrate

delivery in neurosurgical patients. Neurol Res 1997;19:265–

273.

16 Pennings FA, Bouma GJ, Kedaria M, et al. Intraoperative

monitoring of brain tissue oxygen and carbon dioxide

pressures reveals low oxygenation in peritumoral brain edema.

J Neurosurg Anesthesiol 2003;15(1):1–5.

17 Imberti R, Bellinzona G, Langer M. Cerebral tissue PO2 and

SjvO2 changes during moderate hyperventilation in patients

with severe traumatic brain injury. J Neurosurg 2002;96(1):97–

102.

18 Jaeger M, Soehle M, Meixenberger J. Brain tissue oxygen

(PtiO2): a comparison of two monitoring devices. Acta

Neurochir Suppl 2005;95:79–81.

19 Rampling R, Cruickshank G, Lewis AD, Fitzsimmons SA,

Workman P. Direct measurement of pO2 distribution and

bioreductive enzymes in human malignant brain tumors. Int J

Radiat Oncol Biol Phys 1994;15(29-3):427–431.

20 Clavo B, Robaina F, Morera J, et al. Increase of brain tumor

oxygenation during cervical cord stimulation. J Neurosurg Spine

1 2002;96:94–100.

21 Kayama T, Yoshimoto T, Fujimoto S, Sakurai Y. Intratumoral

oxygen pressure in malignant brain tumor. J Neurosurg

1991;74:55–59.

22 Anderson E, Grant R, Lewis SC, Whittle IR. Randomized

Phase III controlled trials of therapy in malignant glioma:

Where are we after 40 years? Br J Neurosurg 2008;22:339–349.

Glioblastoma pathophysiology 453

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vers

ity o

f A

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onal

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y.