British Journal of Anaesthesia 97 (1): 95–106 (2006)

doi:10.1093/bja/ael137 Advance Access publication June 3, 2006

The role of tissue oxygen monitoring in patients with

acute brain injury
J. Nortje1 2* and A. K. Gupta1 2
1
Department of Anaesthesia and 2Department of Neuro Critical Care, University of
Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK
*Corresponding author. E-mail: jn254@cam.ac.uk
Cerebral ischaemia is implicated in poor outcome after brain injury, and is a very common post-
mortem finding. The inability of the brain to store metabolic substrates, in the face of high oxygen
and glucose requirements, makes it very susceptible to ischaemic damage. The clinical challenge,
however, remains the reliable antemortem detection and treatment of ischaemic episodes in the
intensive care unit. Outcomes have improved in the traumatic brain injury setting after the
introduction of progressive protocol-driven therapy, based, primarily, on the monitoring and
control of intracranial pressure, and the maintenance of an adequate cerebral perfusion pressure
through manipulation of the mean arterial pressure. With the increasing use of multi-modal
monitoring, the complex pathophysiology of the injured brain is slowly being unravelled, empha-
sizing the heterogeneity of the condition, and the requirement for individualization of therapy to
prevent secondary adverse hypoxic cerebral events. Brain tissue oxygen partial pressure (PbO2)
monitoring is emerging as a clinically useful modality, and this review examines its role in the
management of brain injury.
Br J Anaesth 2006; 97: 95–106
Keywords: brain, injury, ischaemia; monitoring, intensive care, oxygen; outcome;
oxygenation, oxygen partial pressure

Severe traumatic brain injury (TBI) has a mortality exceed-
ing 40% in the UK; ischaemia playing a significant part.26 27
Neuronal excitotoxicity, oxidative stress, mitochondrial
dysfunction, lipid peroxidation with loss of membrane
integrity and disturbances in ion homeostasis, free radical
production, subsequent inflammation, necrosis and even
apoptosis all play a role in the cascade of post-ischaemic
events.3 101 With targeted therapy having shown promising
reductions in mortality,70 21 11 brain tissue oxygen monit-
oring may provide a further tool not only to elucidate the
pathophysiology, but also individualise therapeutic targets.65
Cerebral oxygenation and cerebral perfusion
pressure targets
Cerebral blood flow (CBF) is regulated by metabolic
requirements under normal conditions, so-called flow-
metabolism coupling, and ensures adequate cerebral oxy-
genation. Temporal patterns of CBF disturbances after trau-
matic brain injury (TBI) have been well documented,2 58
with optimal therapy on the first post-injury day, not neces-
sarily the most appropriate on subsequent days. High intra-
cranial pressures (ICPs) and cerebral hypoxia show strong
correlations with poor outcome,47 making the control of
these parameters with a sufficient cerebral perfusion
pressure (CPP) critically important (see the review by Stei-
ner and Andrews in this postgraduate issue). The exact level
of CPP required following TBI has been subject to much
debate,68 76 86 the latest definitive guidance being the down-
ward revision of the Brain Trauma Foundation’s guidelines
on CPP targets (available from http://www2.braintrauma.
org/guidelines) in 2003, suggesting a CPP target of 60,
rather than 70 mm Hg. The proviso is, however, that in
selected patients, where there is evidence of regional or
global ischaemia, the CPP target may need to be higher.
Individualized CPP optimization, therefore, becomes
dependent on, amongst other things, the monitored levels
of brain oxygenation.
Existing monitors of cerebral oxygenation
Imaging
Positron emission tomography (PET)
Metabolic imaging of the brain after 15O-radioisotope admin-
istration, allows the quantification of CBF, cerebral blood
volume, the oxygen extraction fraction (OEF) and cerebral
metabolic rate for oxygen (CMRO2). Despite limitations,
including the ‘snapshot’ nature of the technique, limited
availability, use of radiation, poor spatial resolution and

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 Nortje and Gupta
the fact that the most unstable patients may not get scanned
(selection bias), PET is still regarded as the ‘gold standard’
for visualizing cerebral oxygen use. Early post-injury PET
has identified the presence of regional ischaemia,13 14 with
quantification of the ischaemic brain volume.
Magnetic resonance spectroscopy (MRS)
MRS is an application of magnetic resonance imaging
(MRI) whereby spectra of metabolic changes in living
tissue are obtained. The outcome predictive value of non-
invasively measuring brain metabolites (biomarkers of
injury processes) using MRS, is increasingly being demon-
strated.22 83 Measurement of adenosine triphosphate (ATP)
using phosphorous spectroscopy (31P-MRS)69 and lactate
using proton spectroscopy (1H-MRS)82 after brain injury
can provide evidence of cerebral ischaemia, while N-acetyl
aspartate represents neuronal integrity. The post-processing
and availability of MRS preclude its routine clinical use at
present.
Bedside
Jugular venous oximetry (Sj O2 )
Catheterization of the internal jugular vein to measure the
oxygen saturation of the effluent cerebral blood at the jugu-
lar bulb, allows assessment of the global oxygenation status
of the brain, providing some insight into the adequacy of
CBF, especially during manoeuvres such as hyperventila-
tion. A significant association between jugular venous desat-
uration and poor neurological outcome exists,24 with poor
outcome in 55% of patients with no episodes of desatura-
tion, 74% with one episode and 90% with multiple episodes.
A shortcoming, however, is the inability of SjO2 to detect
regional ischaemia, with PET evidence13 of approximately
13% of the brain being ischaemic before SjO2 levels decrease
below 50%.
Near-infrared spectroscopy (NIRS)
Penetration of human tissue by light in the near-infrared
band and its resultant absorption and scatter allows assess-
ment of cerebral changes in oxyhaemoglobin (HbO2),
deoxyhaemoglobin (Hb) and cytochrome oxidase. An
attractive non-invasive regional monitor of cerebral oxy-
genation, NIRS has been beset by issues of extra-cranial
blood contamination, light shielding, optimal optode place-
ment, sample volume inaccuracies and the robustness of the
derived algorithms. Spatial resolution and equipment
improvements are addressing these issues, but to date
NIRS has yet to find a clear role in routine clinical practice.4
Intracerebral microdialysis
Microdialysis (the subject of a separate review by Smith and
Tisdall in this postgraduate issue) has become a feasible
clinical bedside technique in the intensive care unit
96
(ICU),33 72 with metabolic patterns34 79 supplying valuable
information on the adequacy of cerebral oxygenation.
Brain tissue oxygen tension (PbO2 )
Improvements in technology, and the pitfalls of the tech-
niques described above, have led to the introduction of brain
tissue oxygenation monitoring.
What is brain tissue oxygen partial pressure?
PbO2 is the partial pressure of oxygen in the extra-cellular
fluid of the brain and reflects the availability of oxygen for
oxidative energy (ATP) production. It represents the balance
between oxygen delivery and consumption, and is influ-
enced by changes in capillary perfusion. Distance from
the supplying capillaries and possible barriers to oxygen
diffusion66 may be particularly important after injury. An
experimental global ischaemia model81 examining the rela-
tionships between PbO2 , local CBF and NIRS-derived
CMRO2 and AVDO2 (arterio-venous difference in oxygen
content) has also suggested that the relative predominance
of arterial or venous vessels in the immediate proximity of
the PbO2 sensor may determine whether coupling exists
between PbO2 and CBF15 19 46 or between PbO2 and OEF
(AVDO2), respectively.
The equipment
The two most commonly used systems to date are the Licox
(GMS, Kiel-Mielkendorf, Germany) and the Neurotrend
(Codman, Johnson & Johnson, Raynham, MA, USA).
With good temporal resolution of acute biological changes,
accomplished by the rapid response rates35 of the PbO2
systems, timely therapeutic interventions and assessment
of the subsequent responses is possible.
795 mV polarization
e− O2
+ −
1
3
0.8 mm 4
2
5
O2
Fig 1 Schematic representation of the tip of the Licox brain tissue
oxygen sensor. 1, Polyethylene tube with diffusible membrane; 2, gold
polarographic cathode; 3, silver polarographic anode; 4, electrolyte
chamber; 5, brain parenchyma. (Adapted from the manufacturer’s
manual.)
 Tissue oxygen monitoring in acute brain injury

1
2
3 6
0.5 mm
4
5

Fig 2 Schematic representation of the tip of the Neurotrend sensor

demonstrating the microporous polyethylene tube (1), the three optical
sensors, namely the PbO2 sensor (2) (ruthenium dye in a silicone
matrix), the PbCO2 sensor (3) (phenol red in a bicarbonate solution), the
pH sensor (4) (phenol red in a polyacrylamide gel) and the
thermocouple (5) (copper and constantan wires) all suspended in phenol
red and polyacrylamide gel (6) and implanted in the brain parenchyma
(7). (Adapted from the manufacturer’s manual.)

Fig 3 Computed tomography image showing the Neurotrend PbO2

Measurement principles sensor (arrow) near the intra-parenchymal ICP monitor in the right
The Licox system provides PO2 measurement, with or with- frontal cerebral white matter.
out brain temperature (thermocouple), in an estimated
7.1–15 mm2 PO2-sensitive area. The PO2 probe utilizes a
Sensors can be inserted, either via a cranial access device
closed polarographic (Clark-type) cell with reversible
sited through a craniotomy, on the ICU, or under direct
electrochemical electrodes (Fig. 1). Oxygen, which has dif-
vision at surgery. Purpose-designed triple lumen cranial
fused from the brain tissue across a semi-permeable mem-
access devices44 allow simultaneous ICP, intracerebral
brane, is reduced by a gold polarographic cathode producing
microdialysis and PbO2 monitoring. Ideally, this should
a flow of electrical current directly proportional to the oxy-
occur in an anatomically similar area of white matter
gen concentration. This oxygen-consuming process is tem-
where PbO2 readings are likely to be more stable. Post-
perature-dependent.
insertion CT confirmation of probe position in the brain
In addition to PbO2 , Neurotrend also offers PbCO2 , pH and
parenchyma (Fig. 3) is important for interpretation of
temperature. Its predecessor, the Paratrend 7, was an
readings. Transiently increasing the F IO2 and observing
intra-arterial monitor which was adapted for intracerebral
the corresponding PbO2 increase, is advised to exclude
use.8 Although Neurotrend has been used both for research
the presence of surrounding micro-haemorrhages or sensor
and clinical purposes, its manufacture has now been discon-
damage at insertion. A ‘run-in’ or equilibration time of up to
tinued. The Neurotrend (Fig. 2) comprises three optical
a half hour is required before readings are stable. Adjust-
sensors (PO2, PCO2 and pH) and a thermocouple contained
ment of insertion depth (when used through an access
within the distal 25 mm of a 0.5 mm diameter microporous
device) is allowed by the Neurotrend, but not the Licox.
polyethylene tube. PO2 measurement occurs by quenching
(reduction) of the intensity of a fluorescent optical emission
from an indicator (ruthenium) in the presence of oxygen
(following light pulses from a blue light emitting diode).
In contrast to the Licox, this process does not consume
oxygen and does not affect the measured oxygen level. Comparison
The pH sensor relies on optical absorption, the local pH
Comparative studies have been carried out to evaluate their
affecting the intensity of light transmitted through an
functioning and reliability under experimental35 and clinical
indicator (phenol red). The PCO2 sensor, similarly, is a
conditions.45 In test conditions, the Licox was slightly more
CO2-selective pH sensor.
accurate, with the Neurotrend under-reading at low PbO2 .
Both sensors displayed slight drift towards lower oxygen
Calibration and insertion concentrations over time, but this was not thought to pro-
Using a sensor-specific pre-calibrated smart card, the Licox hibit long-term use. The Neurotrend measured PbCO2 and
sensor can be inserted without delay, while the less user- pH very accurately. Clinically, the Neurotrend sensor under-
friendly Neurotrend sensor requires a 31 min calibration in read PbO2 (in contrast to the reported overestimation96 of the
a chamber using three calibration gases before insertion. Paratrend 7), and was less robust than the Licox sensor.

97
 Nortje and Gupta

Table 1 Studies relating brain tissue oxygen partial pressure measurements to monitored variables of cerebral oxygenation and blood flow. SjO2 , jugular venous
oximetry; NIRS, near-infrared spectroscopy; rCBF, regional cerebral blood flow; CT, computed tomography; PET, positron emission tomography; TBI, traumatic
brain injury; SAH, subarachnoid haemorrhage; TOI, tissue oxygenation index; L/P, lactate/pyruvate

Comparison modality Authors Study (pathology) Year Findings

Direct local venous Edelman and colleagues20 Animal (normal) 2000 Local tissue and cerebral venous blood Po2, PCO2, pH
gas tensions were highly correlated (P<0.001)
SjO2 Kiening and colleagues53 Human (TBI) 1996 Significant correlation between SjO2 and PbO2 (r2=0.71)
SjO2 Gupta and colleagues29 Human (TBI) 1999 Significant correlation between SjO2 and PbO2 in areas
without focal pathology (r2=0.69)
SjO2 Gopinath and colleagues25 Human (TBI) 1999 Significant correlation between SjO2 and PbO2 (r2=0.58)
NIRS and SjO2 McLeod and colleagues59 Human (TBI) 2003 Comparison of PbO2 , SjO2 and TOI during step changes
in F IO2 : similar patterns of response, but variable
degree and speed
rCBF using xenon CT Doppenberg and colleagues19 Human (TBI) 1997 PbO2 linearly related to regional CBF (r=0.74, P=0.0001)
Local CBF using laser Critchley and Bell15 Animal (SAH) 2003 PbO2 correlated with local CBF (r=0.66, P=0.02)
Doppler flow
rCBF using thermal Jaeger and colleagues46 Human 2005 PbO2 correlated with rCBF (r=0.36, P<0.01)
diffusion (TBI and SAH)
PET Gupta and colleagues30 Human 2002 In normal areas: dPbO2 during hyperventilation
(TBI and SAH) correlates with dPvO2 (calculated from OEF)
(r=0.78, P=0.0035)
Microdialysis Zauner and colleagues102 Human (TBI) 1997 PbO2 correlated with brain glucose (P<0.01), but not lactate
Microdialysis Meixensberger and colleagues62 Human 2001 PbO2 only weak negative correlation with L/P ratio
(TBI and SAH) (SAH: r= 0.185, TBI: r= 0.358)
Microdialysis Sarrafzadeh and colleagues79 Human (TBI) 2003 PbO2 10–15 mm Hg for >5 min: increased glutamate (P=0.03)
PbO2 <10 mm Hg for >5 min: increased glutamate (P=0.007)
and increased lactate (P=0.044)
Microdialysis Hlatky and colleagues34 Human (TBI) 2004 PbO2 <10 mm Hg: increased lactate (P=0.015)

Validation with existing techniques Safety

Establishing the relevance of a monitor requires validation
of the measured variables and their relationships with the
existing clinical and experimental techniques (Table 1).
Clinical utility
Normal values
Normal brain gas tension measurements have been acquired
experimentally, but human measurements have been
restricted to ‘normal’ values during neurosurgery and in
‘normal-appearing’ brain after TBI. A feline study100
revealed a normal PbO2 of 42 (9) mm Hg [PbCO2 of 59
(14) mm Hg, brain pH of 7.0 (0.2)], while a murine
study15 measured a normal PbO2 of 29.4 (12.8) mm Hg.
Human recordings have varied from a PbO2 of 37 (12) mm
Hg [PbCO2 of 49 (5) mm Hg, brain pH of 7.16 (0.08)]36 to a
PbO2 value of 48 mm Hg60 in uncompromised patients
undergoing cerebrovascular surgery.
Hypoxic thresholds
The identification of hypoxic tissue allows the institution of
early potentially corrective interventions, and also provides
meaningful therapeutic end-points. These values need to be
considered in the context of probe type, probe site, under-
lying pathology and duration of hypoxia before irreversible
damage occurs. Various PbO2 hypoxic thresholds (Table 2)
have been proposed.
Initial concerns regarding the invasiveness of these intra-
parenchymal sensors and the risk of haemorrhage and
infection, have proved unfounded. Eleven
studies6 9 17 62 79 91 96–98 102 103 including 552 patients
reported no infections and three iatrogenic haematomas
with only one requiring surgical evacuation. Measurement
accuracy with negligible zero drift was also a consistent
finding.6 17 97 98
Drawbacks
Some of the reported problems include insertion trauma
with subsequent gliosis and the ability to adequately posi-
tion and secure sensors in position. The focal nature of these
monitors must also be emphasized.
Global assumptions of a focal monitor
Jugular venous oxygen saturation (SjO2 ) monitoring
provides global cerebral oxygenation determination and
can be used to calculate the arterio-venous oxygen content
difference. PbO2 sensors are extremely localized, only
sampling approximately 15 mm2 of tissue around the tip.
The positioning of the sensor, however, becomes a vital
question in the interpretation of the readings. In ‘tissue at
risk’ regions near focal pathology, global assumptions can-
not be made and the monitor is purely focal, but when
positioned in areas of seemingly normal tissue, or in
areas of diffuse injury, the PbO2 can be regarded as an

98
 Tissue oxygen monitoring in acute brain injury

Table 2 Human studies proposing hypoxic brain tissue oxygen thresholds. CT, computed tomography; PvO2 , cerebral venous/end-capillary PO2; PET, positron
emission tomography; OEF, oxygen extraction fraction

Sensor Authors Year Proposed threshold How the threshold was determined
[mm Hg (kPa)]

Paratrend 7 Zauner and colleagues102 1997, 1998 25 (3.3) PbO2 of 26 mm Hg  CBF (xenon CT) < 18 ml per 100 g
Doppenberg and colleagues19 per min; all patients with PbO2 <25 mm Hg had a poor outcome
Paratrend 7 Doppenberg and colleagues18 1998 Between 19 and 23 Combined above data with a feline MCA occlusion study and
(2.5 and 3) outcome
66
Neurotrend Menon and colleagues 2004 10 (1.3) Significantly greater diffusion gradients for oxygen
(PvO2 PbO2 ) if PbO2 <10 mm Hg
Neurotrend Johnston and colleagues50 2005 <14 (1.9) Significant linear relationship between PbO2 and PET OEF
(r2=0.21, P<0.05); mean normal OEF=40% associated with
PbO2 =14 mm Hg
Licox Kiening and colleagues53 1996 8.5 (1.1) Regression analysis: SjO2 threshold of 50% correlated with
PbO2 of 8.5 mm Hg
Licox van Santbrink and colleagues98 1996 Between 10 and 15 Significant difference in 6 month outcome at threshold
(1.3 and 2) <5 mm Hg (P=0.04), suggested maintenance of PbO2 between
10 and 15 mm Hg
Licox Valadka and colleagues96 1998 20 (2.7) [6 (0.8)] Tobit regression analysis relating the time below thresholds of
PbO2 with likelihood of death. Much greater likelihood of death,
the longer the PbO2 <20 mm Hg or any time of PbO2 <6 mm Hg
Licox van den Brink and colleagues97 2000 <5 (0.6) for 30 min The relative risk of death was graded. Hypoxic thresholds are
<10 (1.3) for 1 h 45 min expressed as the depth and duration of hypoxia imparting a
<15 (2) for 4 h 50% risk of death

indicator of global oxygenation,25 29 53 97 allowing the use of
PbO2 as an endpoint in the optimization of CPP. Kiening and
colleagues53 compared the use of SjO2 and PbO2 in normal
frontal brain white matter, in 15 patients with severe TBI
showing a strong correlation (r2=0.71). Continuous PbO2
could reliably be monitored twice as long as SjO2 , with
good quality data acquisition 95% of the time with PbO2 ,
as opposed to the 43% for SjO2 . The requirement for repeated
calibrations of the SjO2 measurement system contrasted
starkly with the lack of post-insertion calibration require-
ment of the PbO2 technique.
Dynamic indices
In addition to static baseline PbO2 readings, oxygen regu-
latory mechanisms challenged dynamically, may provide
insight into the underlying pathophysiology and outcome
prediction.
PbO2 reactivity
The increase in PbO2 relative to an increase in arterial PO2 is
termed brain tissue oxygen reactivity. It is believed that this
reactivity is controlled by an oxygen regulatory mechanism
(cf. CBF autoregulation), and that this mechanism may be
disturbed after brain injury. van Santbrink and colleagues99
examined the ‘brain tissue oxygen response’ (the degree of
change in PbO2 in response to changes in PaO2 ) and showed
that greater responsiveness in the first 24 h post-injury was
associated with an unfavourable outcome (P=0.02); with
multiple logistic regression analysis supporting its value
as an independent predictor of unfavourable outcome
(odds ratio 4.8). The effect of PaCO2 on this mechanism
was illustrated experimentally by Hoffman and colleagues42
in dogs where PbO2 reactivity was attenuated during hypo-
capnoea, and emphasizing that when assessing PbO2 reactiv-
ity, effects of PaCO2 need to be considered. To understand
the normal relationships of PbO2 with mean arterial pressure
(MAP), and with changing CO2 concentrations in the
uninjured brain, Hemphill and colleagues32 studied 12
anaesthetized pigs. PbO2 displayed a linear relationship
with CO2 (r2=0.70) and a sigmoid curve with MAP between
60 and 150 mm Hg (r2=0.72), and a linear correlation with
CBF (measured using thermal diffusion probes) during CO2
reactivity testing (r2=0.84). The conclusion was that PbO2 is
strongly influenced by factors regulating CBF, namely CO2
and MAP.
‘PbO2 autoregulation’
Soehle and colleagues84 introduced the concept of ‘PbO2
autoregulation’, defined as the ability of the brain to
maintain PbO2 despite changes in CPP, thereby identifying
appropriate individual CPP targets. Lang and colleagues54
showed a significant correlation (r= 0.61) between static
cerebral autoregulation (determined using CBF velocity in
relation to changing CPP) and cerebral tissue oxygen
reactivity (the rate of change of PbO2 in relation to changing
CPP) suggesting a close link between regulation of CBF and
oxygenation.
Following these findings, manipulation of PbO2 by
altering PaO2 (by F IO2 increases) or altering the CPP (by
MAP increases, ICP decreases, or both) have been inves-
tigated with the view to therapy optimization and potential
prognostication.

99
 Nortje and Gupta
Applications of brain tissue oxygen monitoring
In humans, PbO2 monitoring has predominantly been
applied to the investigation and management of subarach-
noid haemorrhage (SAH) (both on the ICU and during
operation) and severe TBI (see above) on the ICU. Other
applications have included, arterio-venous malformation
(AVM) resection, tumour resection and for studying the
effects of anaesthetic agents.
SAH and vasospasm on the ICU
Despite its invasiveness, the application of PbO2 monitoring
seems attractive for the continuous surveillance and detec-
tion of delayed vasospasm-induced ischaemia in patients
with SAH in the ICU (in contrast to the traditional snapshot
use of TCD). Kett-White and colleagues52 monitored
40 patients (35 after SAH and 5 after complex aneurysmal
surgery) on the ICU with PbO2 and intracerebral microdia-
lysis, but only managed to show weak associations between
episodes of low PbO2 , abnormal microdialysis and outcome.
Possible reasons cited for the marked variability in
measured PbO2 readings were the variable distances from
vasculature (oxygen gradients), grey/white matter
influences (metabolic rates, varying depths attributable to
gyri and sulci) and tissue heterogeneity. A study using
Neurotrend in 10 SAH patients7 (three of whom developed
vasospasm), showed a significant decrease in pH and
increase in PbCO2 (P<0.001), but failed to show ischaemic
PbO2 levels. Meixensberger and colleagues64 prospectively
studied 42 patients presenting with severe grade SAH and
failed to demonstrate the value of PbO2 as an early predictor
of non-survival, citing reasons such as small patient num-
bers, accuracy of probe placement in the affected cerebral
territory, efficacy of the implemented ‘triple H’ (hyper-
volaemia, hypertension, haemodilution) therapy, and the
possibility that oxygen consumption may have been more
depressed than CBF, resulting in unchanged PbO2 values.
The jury, therefore, remains out on the value of PbO2 mon-
itoring as an early warning of cerebral vasospasm in SAH
patients on the ICU.
Aneurysm surgery
Intraoperative use of PbO2 monitoring is both feas-
ible23 36 39 40 43 51 92 and is a sensitive indicator of cerebral
tissue at risk. Severe bleeds (Fisher grade 3) also signifi-
cantly decrease PbO2 (P<0.05).43 Correctly positioned PbO2
monitoring allows not only assessment of the effect and
reversibility of temporary aneurysm clipping, but can also
be indicative of the correct positioning of the subsequent
permanent clip.23 Hypoxic PbO2 levels confirmed comprom-
ised perfusion detected on preoperative single photon emis-
sion computed tomography (SPECT) and cerebral
angiography.36 In a study of 46 patients undergoing crani-
otomy for aneurysm clipping,51 the majority of 31 patients
who required temporary clipping of the parent vessel,
showed decreases in PbO2 , with a level of PbO2 <8 mm
100
Hg for 30 min being predictive of cerebral infarction.
Another study92 found that PbO2 monitoring during
aneurysm clipping supplemented somatosensory evoked
potential (SEP) monitoring in identifying ischaemia, espe-
cially in those patients where the baseline SEP was absent.
AVM surgery
PbO2 measurement has been used to investigate the oxy-
genation of cerebral tissue supplied by vessels with
AVMs.38 In total, 13 patients undergoing resection of
AVMs were compared with 8 non-ischaemic patients under-
going aneurysmal surgery (the controls). Low PbO2 , but
normal PbCO2 and pH (in contrast with raised PbCO2 and
acidosis seen in acute occlusive disease with ischaemia39)
before AVM resection suggested low perfusion and chronic
hypoxia with possible metabolic adaptation and subsequent
hypometabolism, while the marked PbO2 increases
post-resection indicate hyperperfusion with its attendant
problems. Apart from enhancing the understanding of
AVM pathophysiology, this study reaffirms the feasibility
of intraoperative PbO2 monitoring.
Tumours
The extent and nature of the effects of oedema on brain
tissue oxygen surrounding tumours was investigated peri-
operatively in 19 patients.71 MRI-based stereotaxis was used
to guide sensor placement into the peritumoral area before
craniotomy and the effects of dural opening and resection
on the PbO2 was noted. In patients with swelling, PbO2
increased significantly on dural opening (P<0.05), and post-
resection (P<0.05), implying the presence of ischaemic pro-
cesses with oedema. This emphasizes the importance of
maintaining adequate CPP in patients undergoing brain
tumour surgery. PbO2 monitoring during awake craniotomy
for tumour resection has also been reported.93
Anaesthetic drug pharmacodynamics
Studies investigating the dose effects of anaesthetic agents
such as isoflurane,41 desflurane37 and propofol48 on cerebral
autoregulation and oxygenation to levels of EEG burst-
suppression have also utilized PbO2 monitoring. The inhala-
tional agents demonstrate a dose-related loss of autoregu-
lation with corresponding increase in PbO2 as long as the
CPP is maintained, while propofol displays no such changes
and flow-metabolism coupling remains intact.
Therapeutic and research interventions
The clinical utility and temporal responsiveness of PbO2 to
fraction of inspired oxygen (F IO2 ) increases, PaCO2 changes
(hyper- and hypoventilation) and haemorrhage to 70% blood
loss or cardiac arrest with immediate subsequent resuscita-
tion, were experimentally validated by Manley and col-
leagues.57 In addition, investigation of pathophysiological
 Tissue oxygen monitoring in acute brain injury

200
ABP 180 ABP
160
140
95.6 120 133
100
80
60
40
20
mm Hg 0
50
ICP 45 ICP
40
24.4 35 24.2
30
25
20
15
10
5
mm Hg 0
120
CPP 110 CPP
100
71.1 90
109
80
70
60
50
mm Hg 40
4
PtO2 PtO2
3
0.500 2.78
2

kPa 0
30/5 10:00 30/5 10:15 30/5 10:30

Fig 4 Bedside monitoring of a patient with severe TBI with the Neurotrend PbO2 sensor placed near a cerebral contusion. Increasing the cerebral
perfusion pressure (CPP) from around 70 mm Hg to above 100 mm Hg reverses the cerebral hypoxia (ABP, mean arterial blood pressure; ICP,
intracranial pressure; PtO2 = PbO2 ; kPa, kilopascals).

mechanisms after brain injury in studies combining PbO2
monitoring with PET, have proposed the presence of micro-
circulatory abnormalities with significant gradients for oxy-
gen diffusion in injured tissue.66 Structural evidence for
these pathophysiological changes has also been well
documented.77 As more data are accumulated regarding
hypoxic thresholds, and the clinical and outcome signifi-
cance of PbO2 in various clinical situations is established,
the changes in baseline PbO2 levels in response to potential
therapeutic or research interventions gives weight to their
clinical value. Interventions include the following.
Elevation of CPP
A comparative study using dopamine or norepinephrine to
elevate CPP from 65 to 85 mm Hg, showed no significant
increase in the PbO2 values monitored in predominantly
normal-appearing brain.49 However, targeted PbO2 sensors
in CT hypodense lesions in nine patients89 (with hypoper-
fusion confirmed with SPECT) revealed significant
improvements in PbO2 readings with induced hypertension
(r2=0.74). Significantly higher PbO2 has been shown at a
CPP >70 mm Hg than <70 mm Hg in TBI patients
(P<0.001)9 (cf. Fig. 4).
Hyperventilation
An experimental study in 12 healthy pigs10 comparing
PbO2 (Licox), rCBF (thermal diffusion system) and meta-
bolic microdialysis markers at baseline, during moderate
(PaO2 =30 mm Hg) and profound (PaO2 =20 mm Hg)
hyperventilation revealed that both moderate and profound

101
 Nortje and Gupta
hyperventilation may cause insufficient regional oxygen
supply and anaerobic metabolism. The value of PbO2 as a
monitor of excessive hyperventilation (cf. SjO2 ) was
illustrated in a head injury study of 90 patients6 where
the PaCO2 was decreased with hyperventilation and PbO2
decreased significantly (P<0.001). Importantly, the risk of
secondary cerebral ischaemia with hyperventilation
increased over time.
Hypothermia
Despite the negative findings of the National Acute Brain
Injury Study: Hypothermia12 (no improvement in outcome
using hypothermia to 33 C within 8 h of TBI) and the
Intraoperative Hypothermia for Aneurysm Surgery Trial94
(no improvement in neurological outcome using intraoper-
ative hypothermia in good grade SAH), hypothermia is
thought to reduce secondary brain injury following TBI
by metabolic suppression and reduction of inflammation,
free radicals, cytokines and excitatory amino acids. PbO2
and direct brain temperature were measured in 58 patients
after severe TBI,85 and revealed decreases in the PbO2 with
mild hypothermia (34–36 C) accompanied by decreases in
ICP and PbCO2 and increases in brain pH. Decreased meta-
bolic requirements and lowering of the PbO2 critical thresh-
old were concluded. Another PbO2 study in 30 patients28
indicated that 35 C might be the optimal temperature after
severe TBI.
Decompressive craniectomy
In patients with intractable intracranial hypertension, des-
pite maximal medical therapy, surgical (either bi-frontal or
unilateral) removal of a part of the skull may be considered.
The benefits of this technique and whether it offers any
advantage in outcome and quality of outcome over the
use of barbiturate coma, although not yet known, is
currently the subject of the multi-centre RESCUE-ICP study
(Randomized Evaluation of Surgery with Craniectomy for
Uncontrollable Elevation of IntraCranial Pressure; avail-
able at http://rescueicp.com/). Recent studies have added
the use of PbO2 monitoring to the traditional ICP/CPP para-
meters in assessing the impact of this last-resort procedure.
A retrospective review91 of 20 ICP and PbO2 monitored
SAH patients who ultimately underwent surgical hemi-
craniectomy for intracranial hypertension, revealed 12
patients in whom PbO2 decreases to <10 mm Hg were the
first sign of deterioration. Most notably, hypoxic PbO2 read-
ings were present 13.4 h (mean) before development of
intracranial hypertension in nine patients hinting at an
important potential therapeutic window. Another decom-
pressive hemi-craniectomy study87 revealed favourable
decreases in ICP and increases in CPP, but also sustained
improvement in cerebral oxygenation. Patients with severe
brain hypoxia before surgery were likely to have poorer
outcomes, raising the possibility of using PbO2 monitoring
to select the patients who might benefit most from surgical
102
decompression. Subsequently, a study75 used PbO2 <10 mm
Hg during refractory raised ICP as an indication for hemi-
craniectomy in five patients. It documented the significant
reduction in ICP (P<0.039) and increase in PbO2 (P<0.041)
during the perioperative period, noting the importance of
dural enlargement (by means of a dural graft) on the meas-
ured parameters. The authors proposed that hypoxic PbO2
values may have heralded the onset of cytotoxic brain
oedema, highlighting the role of PbO2 in the timing of sur-
gical intervention.
Hyperoxia
The therapeutic use of normobaric hyperoxia, to counter
the effects of cerebral ischaemia by facilitating oxidative
metabolism, has received increasing attention in the man-
agement of severe TBI.1 5 55 Although attractive in its ease
of use (by increasing the FIO2 in ventilated patients), the
target population, the dose and the duration of hyperoxia
have yet to be defined. While studies utilizing PbO2 and
microdialysis monitoring agree universally on the elevation
of the PbO2 with this intervention, and have documented the
resultant biochemical effects,56 67 73 74 95 the clinical benefit
of this therapy needs further elucidation.
Other cerebral tissue parameters
This review has focused on oxygen partial pressure in the
tissue, but the use of the Neurotrend sensor also allowed
PbCO2 and pH monitoring. The relationships of these vari-
ables to other brain parameters have been well documented
in a study by Clausen and colleagues9 where they demon-
strated that PbCO2 was significantly higher at 6 h post-injury
in patients with poor outcomes compared with patients with
good outcomes (P<0.05). They also showed that PbCO2 was
significantly higher at a CPP below 70 mm Hg as opposed to
higher (P<0.0001), and also significantly higher at a PbO2
below 10 mm Hg as opposed to higher (P<0.0005). These
findings were in the face of a stable PaCO2 . Brain pH dif-
ferences at these CPP and PbO2 thresholds were also sig-
nificant (both P<0.0001). Low brain pH has also been
correlated with adverse outcome (P=0.003).31 These para-
meters may, therefore, also provide useful end-points in
optimization of therapy. Brain temperature measurement
(available with both Neurotrend and Licox) has allowed
investigation of hyperthermia78 90 and hypothermia.28 85 103
Cerebral oxygenation and outcome prediction
The theme of brain oxygen manipulation, and its effect on
patient outcome, was first addressed in 1998 when Cruz16
demonstrated a significant improvement in 6 months out-
come in a group of 178 patients who underwent jugular
oximetry monitoring and manipulation of oxygen extrac-
tion, compared with a group of 175 patients receiving
ICP/CPP-guided treatment alone (P<0.00005). However,
 Tissue oxygen monitoring in acute brain injury
Table 3 TBI studies demonstrating the value of brain tissue oxygen tension in outcome prediction (dichotomized outcome=alive vs dead/persistent vegetative state)
Authors Year No. of
patients
van Santbrink and colleagues98 1996 22
Doppenberg and colleagues19 1997 25
Zauner and colleagues102 1997 24
Valadka and colleagues96 1998 39
van den Brink and colleagues97 2000 101
to enable reliable continuous SjO2 readings unaffected by
head movement and motion artifacts, all of the patients in
this group wore cervical collars.
PbO2 monitors are much less prone to accidental displace-
ment and are not affected by head movement, resulting in
considerably less maintenance post-insertion. The value of
adding PbO2 measurement to the standard ICP/CPP-guided
therapy has been assessed in two prospective observational
studies.61 88 Meixensberger and colleagues61 compared the
effect of keeping PbO2 above 1.33 kPa (10 mm Hg) as a
secondary therapeutic target in ICP/CPP-guided manage-
ment algorithms in 53 patients, to a historical control
group of 40 patients receiving ICP/CPP-guided manage-
ment alone. PbO2 was successfully maintained at higher
levels in the test group, and although there was no statist-
ically significant difference in 6 month outcome, there was
a positive trend in the PbO2 -guided group. Stiefel and
colleagues88 similarly compared a traditional ICP/
CPP-guided group (25 patients) to a PbO2 -guided group
(28 patients) targeting a PbO2 of greater than 3.33 kPa
(25 mm Hg). They evaluated hospital outcome and demon-
strated a significant reduction in mortality in the PbO2 -
guided group (P<0.05), and better functional outcomes in
this group. Meixensberger and colleagues63 also showed a
correlation between low PbO2 in the acute post-injury phase
with poor neuropsychological performance 2–3 yr later in
40 patients.
The possible value of PbO2 -guided therapy may also have
been demonstrated by a study80 comparing 36 patients with
isolated severe head injuries to 44 patients with severe head
injuries and severe extra-cranial injuries; both groups
managed with ICP/CPP/PbO2 protocols and late surgical
intervention for extra-cranial injuries. Revealing no signi-
ficant difference in 6 month or 1 yr outcome, it contrasted
with previous reports of increased mortality in head injured
patients with significant co-existing extra-cranial injuries.
Numerous severe head injury studies have correlated low
PbO2 with adverse outcome (Table 3). There are no
Sensor Outcome prediction
Licox PbO2 <5 mm Hg in the first 24 h post-injury, negatively correlated
with 6 month dichotomized outcome (P=0.04, Fisher’s exact test).
Oxygen reactivity was also significantly lower in the good outcome
group (P=0.02, Mann–Whitney test)
Paratrend All patients with a PbO2 <25 mm Hg, measured at a mean of 27 h
post-injury, died or remained in a vegetative state
Paratrend If mean PbO2 <15 mm Hg, patients died within 36 h.
PbO2 was the strongest predictor of outcome (multiple logistic
regression analysis)
Licox Mortality increased with increasing time spent with a PbO2 <15 mm Hg,
or any PbO2 values <6 mm Hg (Tobit regression analysis using
maximum likelihood methods)
Licox PbO2 <10 mm Hg for >30 min was an independent predictor of death or
unfavourable outcome (multiple logistic regression analysis).
Depth and duration of tissue hypoxia are independently related to 6 month
outcome
randomized controlled trials of PbO2 -guided therapy to
date. Given the clinical feasibility and the increasing
evidence of worsened outcome with low brain PbO2 ,
prospective randomized PbO2 -directed studies are now
essential.
The future
The invasiveness of the PbO2 technique will always be an
issue and may limit its usefulness in patients with coagu-
lopathy, for instance. Combining parameters such as ICP
and PbO2 into a single probe may reduce the number of
probes inserted, but the ideal remains a non-invasive mon-
itor. Better integration of the collected data with continuous
online derived indices at the bedside may also facilitate
patient optimization. Routine use of dynamic challenges
(e.g. increases in CPP or F IO2 when cerebral hypoxia
presents), may identify individualized therapeutic targets.
Conclusion
Brain tissue oxygen partial pressure measurement contrib-
utes to the prevention of delayed cerebral damage after TBI
and SAH. The integrated, continuous monitoring of PbO2 is
now accepted as being safe and feasible. Reliable bedside
PbO2 monitoring, both at baseline, and during the course of
interventions such as CPP manipulation and hyperventila-
tion, complements the use of existing cerebral monitors, and
with the increasingly multi-modal approach of cerebral
monitoring and data recording, may allow appropriate indi-
vidualization of therapy. The rapid response of PbO2 sensors
to altering tissue oxygen levels, together with further PbO2
threshold data, will allow more accurate identification of
adverse cerebral conditions. Coupled with modalities
such as ICP, transcranial Doppler and brain chemistry
(microdialysis), more timely intervention and prognostica-
tion may be allowed. PbO2 measurement, therefore, is emer-
ging as a useful clinical tool and, taken within the context of
103
 Nortje and Gupta
underlying pathology, probe positioning, and responses and
trends, there is mounting evidence that PbO2 -guided therapy
may bring us a step closer to the goal of outcome improve-
ment after brain injury.
Acknowledgement
J.N. is funded by a British Journal of Anaesthesia/Royal College of
Anaesthetists Fellowship.
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