Society for Technology in Anesthesia

Section Editor: Maxime Cannesson

Factors Affecting the Performance of 5 Cerebral

Oximeters During Hypoxia in Healthy Volunteers
Philip E. Bickler, MD, PhD, John R. Feiner, MD, and Mark D. Rollins, MD, PhD
BACKGROUND: Cerebral oximetry is a noninvasive optical technology that measures frontal cortex
blood hemoglobin-oxygen saturation. Commercially available cerebral oximeters have not been evaluated independently. Unlike pulse oximeters, there are currently no Food and Drug Administration
standards for performance or accuracy. We tested the hypothesis that cerebral oximeters accurately measure a fixed ratio of the oxygen saturation in cerebral mixed venous and arterial blood.
METHODS: We evaluated the performance of 5 commercially available cerebral oximeters: the
EQUANOX 7600 in 3- and 4-wavelength versions (Nonin Medical, Plymouth, MN), FORE-SIGHT
(Casmed, Branford, CT), INVOS 5100C (Covidien, Boulder, CO), and the NIRO-200NX (Hamamatsu
Photonics, Hamamatsu City, Japan) during stable isocapnic hypoxia in volunteers. Twenty-three
healthy adults (14 men, 9 women) had sensors placed on each side of the forehead. The subjects
inspired oxygen (Fio2) was then changed to produce 6 steady-state arterial oxygen saturation (Sao2)
levels between 100% and 70%, while end-tidal CO2 was maintained constant. At each plateau,
simultaneous blood samples from the jugular bulb and radial artery were analyzed with a hemoximeter (OSM-3, Radiometer Medical A/S, Copenhagen, Denmark). Each cerebral oximeters bias
was calculated as the difference between the instruments reading (cerebral saturation, Sco2) with
the weighted saturation of venous and arterial blood (Sa/vo2), as specified by each manufacturer
(INVOS: 25% arterial/75% venous; FORE-SIGHT, EQUANOX, and NIRO: 30% arterial/70% venous).
RESULTS: Five hundred forty-two comparisons between paired blood samples and oximeter
readings were analyzed. The pooled root mean square error was 8.06%, a value higher than for
pulse oximeters, which is 3% by Food and Drug Administration standards. The mean % bias
SD (precision) and root mean square errors were: FORE-SIGHT 1.76 3.92 and 4.28; INVOS
0.05 9.72 and 9.69; NIRO-200NX 1.13 9.64 and 9.68; EQUANOX-3 2.48 8.12 and
8.47; EQUANOX-4 2.84 6.27 and 6.86. The FORE-SIGHT, NIRO-200NX, and EQUANOX-3
had significantly more positive bias at lower Sao2. The amount of bias during hypoxia was
reduced when the bias was calculated on the basis of difference between oximeter reading and
the arterial and mixed venous saturation difference rather than the weighted average of blood
saturation, indicating that differences in the ratio between arterial and venous blood volumes
account for some of the positive bias at low saturation. Dark skin pigment tended to produce
more negative bias in all instruments but bias was significantly larger than zero only for the
FORE-SIGHT oximeter. Bias was significantly more negative in women for INVOS and EQUANOX
devices but not for the FORE-SIGHT device.
CONCLUSIONS: While responsive to desaturation, cerebral oximeters exhibited large variation
in reading errors between subjects, with mean bias possibly related to variations in the ratio
of arterial and venous blood in the sampling area of the brain. This ratio is probably not fixed,
as assumed by the manufacturers, but dynamically changes with hypoxia. Better understanding
these factors could improve the performance of cerebral oximeters and help establish saturation or blood flow thresholds for brain well-being.(Anesth Analg 2013;117:81323)

erebral oximetry is a noninvasive, optical technology

that integrates frontal cortex blood hemoglobin-oxygen
saturation. The technology evolved from efforts to

From the Department of Anesthesia and Perioperative Care, SeveringhausRadiometer Research Laboratories and the UCSF Hypoxia Research Laboratory, University of California at San Francisco, San Francisco, California.
Accepted for publication April 3, 2013.
Funding: Supported by funds derived from the testing of pulse oximeters,
but no manufacturer directly supported the study.
The authors declare no conflict of interest.
Reprints will not be available from the authors.
Address correspondence to Philip Bickler, MD, PhD, Sciences 255, Box 0542,
University of California, 513 Parnassus Ave., San Francisco, CA 94143-0542.
Address e-mail to bicklerp@anesthesia.ucsf.edu.
Copyright 2013 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318297d763

October 2013 Volume 117 Number 4

measure the state of oxygen metabolism in tissues by assessing the near-infrared absorption of cytochrome C oxidase, a
function of oxygen partial pressure in the mitochondrion.1,2
The assessment of cytrochrome oxygenation state in complex
tissues in vivo is challenging because the near-infrared absorbance of hemoglobin overlaps with that of the cytochromes.
Furthermore, hemoglobin is present in most tissue regions
of interest at far higher concentrations than cytochrome C. It
is therefore not surprising that near-infrared spectroscopy of
cytochromes is subject to substantial errors due to difficulty
assigning the correct computational algorithm to account for
oxy- and reduced hemoglobin in tissue.3,4 In contrast, oxygen
use with insufficient oxygen delivery will lead to an increase
in reduced hemoglobin, and since hemoglobin chromophores dominate the near-infrared absorption spectrum, the
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813

Cerebral Oximetry Performance During Hypoxia

estimation of hemoglobin-oxygen saturation should be less

susceptible to these issues and errors. Similar to pulse oximetry, it should theoretically be possible to calibrate a cerebral
oximeters reading (regional saturation, rSo2 or the cerebral
oximeters estimate of regional saturation, Sco2) to the ratio
of oxy- and deoxyhemoglobin in the vasculature. An in vivo
calibration can be accomplished with direct measurement of
cerebral venous and arterial saturation in blood samples. This
calibration, incorporated into the calculation algorithm that
determines the displayed value of Sco2, should theoretically
reduce the interfering effects of different hemoglobin concentrations and variations in tissue light transmission. This calibration approach assumes that all individuals have the same
ratio of cerebral mixed venous and arterial blood within the
tissue where saturation is measured.
In recent years, the clinical use of cerebral oximetry has
expanded considerably and there are at least 4 companies
selling cerebral oximeters in North America. Clinical interest in the devices is substantial, in part because of the hope
that brain oxygenation state assessed by cerebral oximeters
might predict important long-term outcomes and complications. Among the outcomes predicted by low cerebral oximeter readings include neuropsychiatric impairment,5 stroke in
cardiac surgery patients,6 organ dysfunction and mortality,7,8
and length of hospital stay.9 Similarly, cerebrovascular insufficiency as assessed by cerebral oximetry10 may be a marker for
poor clinical outcome in cardiac surgery patients. However,
it remains unclear whether cerebral oximetry serves as a
reliable clinical monitor in carotid endarterectomy,11 head
injury,12 and in the pediatric population.13 Contamination of
signals from extracranial blood in the sampled area also complicates the clinical utility of this technology.14,15
The comparative accuracy of cerebral oximeters has not
been independently evaluated in detail since a study by Kim
et al.16 more than a decade ago. The Kim et al.16 study compared the rSo2 estimated by the INVOS 4100A cerebral oximeter (Somanetics Corp, Troy, MI) with that of jugular venous
blood, and not the weighted average of arterial and venous
blood that is the stated basis for cerebral rSo2 determination in
currently available instruments. There are currently no Food
and Drug Administration (FDA) standards for accuracy of
cerebral oximeters as with pulse oximeters. This technology
differs from pulse oximetry in the important respect that it
cannot provide an absolute index of saturation. This explains
our clinical observation that even in well-oxygenated and
normal subjects or patients, repeated readings in the same
patient vary substantially from one another, and that during
hypoxia the differences persist and may expand. Importantly,
the causes of the variation in the difference between repeated
readings between subjects are not apparent. We believe that
identifying the contributing factors to interindividual variability in cerebral rSo2 could improve cerebral oximeter
technology. Accordingly, the purpose of this study was to
determine and quantify the factors that contribute to bias
between cerebral oximeter reading and the weighted average of cerebral mixed venous and arterial blood saturation in
healthy subjects during isocapnic hypoxia.

subjects gave informed written consent. The pool of subjects

were healthy nonsmoking men and women, from 20 to 49
years of age, willing to volunteer for the study for a nominal
payment. The selected group of subjects was gender and ethnically balanced, following the U.S. FDA requirements for standard studies of pulse oximeter accuracy.a With an enrollment
target of 25 subjects, we enrolled 23 healthy adult subjects, 14
men and 9 women, with a range of skin pigmentation. This
enrollment target was set because studies to evaluate pulse
oximeter accuracy typically involve 10 to 12 subjects per U.S.
FDA guidelines, and we expected cerebral oximeter errors to
be larger than for finger pulse oximeters. Skin pigment was
classified as light, intermediate, or dark, as in a previous publication concerning the effect of skin pigment of pulse oximeter
accuracy.17 Pregnancy in women was excluded by medical history. The data were analyzed after completion of the study.
A 22-gauge radial arterial cannula was placed using
1% lidocaine local anesthesia in either wrist of each subject
for arterial blood sampling and continuous measurements
of arterial blood pressure. The volunteers were placed in
the Trendelenburg position and a 20-gauge 5-inch catheter
(Arrow International, Reading, PA) was inserted retrograde
into the right internal jugular vein, using sterile technique,
local anesthesia with 1% lidocaine, and ultrasound guidance
(Site Rite, Dymax, Pittsburgh, PA) to identify the vein. The
catheter was advanced the entire 5 inches or until the subject
noted a sensation in the jaw or ear area, indicating that the tip
of the catheter was in the jugular bulb. After catheter insertion, ultrasound was used to verify the location of the catheter
tip in the jugular bulb and further adjustment done as needed.
We evaluated the accuracy performance of 5 commercially available cerebral oximeters in routine, worldwide
use: the EQUANOX 7600 in 3- and 4-wavelength versions
(Nonin Medical, Plymouth, MN), FORE-SIGHT (Casmed,
Branford, CT), INVOS 5100C (Covidien, Boulder, CO), and
the NIRO-200NX (Hamamatsu Photonics, Hamamatsu
City, Japan). The oximeter sensors, 2 at a time per subject,
were randomized to the right or left side of the forehead and
covered with dark cloth and aluminum foil to shield them
from ambient light. Each subject had all 5 cerebral oximeter
sensors placed, in random order, during 3 runs of hypoxia.
Its sensor was adjusted if an oximeter did not display a saturation value. The output of each oximeter was recorded
both by serial datastream acquisition and by manually
recording the display reading for rSo2 from each device, as
a backup. The serial data output was used for analysis.
To measure cerebral oximeter performance during
hypoxia, the fraction of inspired oxygen (Fio2) was stepwise
changed to produce stable oxygen saturation (Sao2) levels
between 70% and 100%, while the end-tidal CO2 was continually monitored on a computer screen and maintained
constant by adding CO2 to the breathing gas as needed. We
used a semi-open rebreathing system that allowed very stable plateaus of oxygen saturation and CO2 partial pressure.
Blood samples from the jugular bulb and radial artery were
simultaneously collected. Before each blood sample, dead
U.S. Food and Drug Administration. Pulse Oximeters-Premarket Notifications
Submissions [510(k)s]-Guidance for Industry and Food and Drug Administration Staff. Available at http://www.fda.gov/downloads/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/UCM081352.pdf.
Accessed May 21, 2013.

METHODS

The University of California at San Francisco (UCSF)

Committee on Human Research approved the study, and all

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space blood was removed from the catheters and discarded. Arterial and venous blood samples were analyzed
with a multiwavelength optical blood analyzer (OSM-3,
Radiometer Medical A/S, Copenhagen, Denmark) to determine oxygen saturation (Sao2 and Svo2).
The rate of blood draw from the jugular catheter was 1
mL over 30 seconds, to reduce reflux of nonjugular bulb
blood into the sample.18 The ratio of saturation in arterial
and venous blood claimed by each instruments manufacturer was used to calculate the reference saturation. For
INVOS, the weighting ratio was 25/75 arterial/venous and
for the others 30/70. The accuracy of the instruments could
then be calculated from this reference saturation and the
reading from the cerebral oximeter.
At the beginning of each study, 1 arterial and 1 venous
blood sample was drawn from each subject while they
breathed room air. Hypoxemia was then induced to 5 to 6
different targeted stable Sao2 levels (between 70% and 100%,
based on end-tidal gas analysis) by having subjects breathe
mixtures of nitrogen, air, and CO2 according to an established
protocol, previously detailed.17 Each Sao2 level was maintained at a steady state for at least 60 seconds, allowing oximeter readings to stabilize, at which point 2 simultaneous arterial
and 2 jugular bulb venous blood samples were obtained, 30
seconds apart during the steady state. The target saturation
values below room air, and nominal Pao2 corresponding to
each were as follows: 92%, 63 mmHg; 87%, 53 mmHg; 82%,
46 mmHg; 77%, 42 mmHg; and 70%, 37mmHg.

Hypotheses and Statistics

We did not have preliminary data to perform a power

analysis. Twenty-five subjects were chosen to double the 12
subjects typically required for U.S. FDA evaluation of pulse
oximeter accuracy.
The following hypotheses and statistical approaches
were used in this study:
Hypothesis 1
Cerebral oximeters have a bias that is not affected by the
reference (weighted) saturation range. The weighting is
specified by each manufacturer (75%25% cerebral mixed
venous to arterial for INVOS, 70%30% for the others). The
following standard descriptive statistics for performance
were calculated: the bias for each cerebral oximeter reading
(oximeter reading-weighted saturation), the mean bias of all
readings for each instrument, a regression line for a plot of
bias versus weighted saturation (the reference), precision
(standard deviation of the bias), limits of agreement and the
root mean square error (Arms). The Arms was calculated for
different ranges of reference oxygen saturation (weighted
value of Sao2 and Svo2) as the square root of the arithmetic
mean of the individual errors. This statistic is used as a standard measure of performance expressing the variability of
the errors in measurements, including pulse oximeter errors.
The linear regression of the bias plots was analyzed
according to the method of repeated measures by entering the
subject number as a random effect in the model. The betweensubject variation (sum of squares), within-subject variation
(variation due to differences in the reference saturation), and
error (residual) were determined for each cerebral oximeter.
Limits of agreement for the bias plots were calculated with the

October 2013 Volume 117 Number 4

methods of Bland and Altman19 with adjustments for multiple

measurements for each individual. In subsets within ranges
of the reference saturation without sufficient numbers of
data points, limits of agreement were calculated as 1.96SD.
Components of the model (between subject, Sao2/Svo2 reference, and residual error) were determined.
Data were also analyzed by comparing the mean bias
within ranges of reference saturation (30%50%, 50%70%,
and 70%90%). The Shapiro-Wilk test was used to test the
normality of the distribution of individual bias values.
This statistic revealed that distribution of bias was slightly
skewed in all 5 instruments (all P < 0.01). However, the differences in mean bias for defined ranges of reference saturation (Sao2/Svo2) were sufficiently large that we were
justified in using analysis of variance for repeated measures
without any data transformation. Tukey-Kramer honest significant difference was used for multiple comparisons.
Hypothesis 2
Changes in the mean bias (difference between cerebral
oximeter reading and weighted measurement of cerebral
mixed venous and arterial blood) of cerebral oximeters during hypoxia are influenced by the assumption that cerebral
oximeters detect the saturation of a fixed ratio of cerebral
mixed venous and arterial blood. This means that bias calculated based on the arterial-venous saturation difference
(Sao2 Svo2) differs from the bias calculated based on the
weighted difference of measured saturations. This hypothesis was tested by determining the significance of slopes of
plots of bias plots calculated with weighted saturation and
with bias calculated by the arterial to venous (A V) difference. If the slope was significant in one instance and not in
the other, this would support the hypothesis.
An early inspection of the data revealed that there was
large reading variation (i.e., bias) among different subjects,
but that within subjects the bias was distributed much more
tightly. For example, one reason why an individuals baseline reading of cerebral saturation may be different from
anothers is that he/she has a different ratio of venous and
arterial blood in the sensor field; this condition creates an
offset in bias compared with the mean bias of all subjects.
This effect was described, not by a particular statistical test,
but by partitioning the percentage of variation in bias values
caused by between-subjects variation and the percentage of
variation in bias caused by changes in oxygenation (changing arterial saturation between 100% and 70%). This was
calculated using the JMP statistical package (SAS Institute,
Cary, NC), using the same repeated-measures model in the
regression analysis (Fig.1). The output supplies the sum of
squares for the components in the model: subjects, the X
variable (the reference saturation), and the residual error.
Hypotheses 3 and 4
Cerebral oximeter mean bias varies by skin color and
gender. The effect of gender and skin color on bias was
examined with a multivariate analysis. To construct a
multivariate analysis examining the impact of skin color
and gender on bias, we started with the repeated-measures model described above, analyzing bias versus the
weighted (reference) saturation (Sao2/Svo2). To this, we
added the other variables, i.e., skin pigment or gender.

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Cerebral Oximetry Performance During Hypoxia

Figure 1. Bias of 5 cerebral oximeters during hypoxia (difference between cerebral

oximeter reading [Sco2] and weighted average of arterial and cerebral mixed venous
blood [Sa/vo2]). The weighting of cerebral mixed venous and arterial blood was
assumed to be 75%/25% for the INVOS
instrument and 70%/30% for the others.
Panel E contains the combined data from
all instruments. The significance of the
slopes of the regression lines are based
on repeated-measures analysis. The 95%
confidence intervals (CIs) for the slope and
the P value are also given. LOA = limits of
agreement.

The interaction term was the reference multiplied by either

variable. Although the data were not strictly normally distributed as assessed by the Shapiro-Wilk test, we used a
linear model for the multivariate analysis because the
method appeared sufficient to identify the effects of skin
or gender on the bias. For example, log transformation of
the bias did not improve the statistical significance of the
effect of skin pigment or gender in the model. The model
also did not account for unequal covariances (sphericity). These inadequacies could produce a type 2 error,
but would not have a significant likelihood of producing
a type 1 error. The Tukey-Kramer honest significant difference method was used to assess multiple comparisons
among the 3 different categories of skin color (light, intermediate, dark). Because of the assumptions related to bias
distribution, we set significance at a P < 0.001.
Data are reported as mean SD or mean (95% confidence
interval [CI]) as indicated. Data were analyzed with JMP
10.0 (SAS Institute) or using custom-generated functions
in Excel 14.2.2 (Microsoft, Redmond, WA). For all statistical
tests, P < 0.05 was considered significant.

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RESULTS
Subject Demographics

Table 1 is a demographic summary of the 23 subjects

enrolled in the study.

Table 1.Demographics
Age (y)
Gender (male/female)
Weight (kg)
Body mass index (kg/m2)
Average hemoglobin (g/dL)
Skin
Light
Intermediate
Dark
Ethnicity
Caucasian
Asian
Hispanic
African American
Mixed/Multiethnic

28.2 4.6
14 (61%)/9 (39%)
72.2 12.0
23.4 2.3
12.8 1.4
12 (52%)
9 (39%)
2 (9%)
12
4
3
2
2

(52%)
(17%)
(13%)
(9%)
(9%)

Data are mean SD or n (%).

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Bias of Cerebral Oximeter Readings Compared

With Weighted Blood Saturation Measurements
During Hypoxia

Five hundred forty-two comparisons between pairs of arterial and venous blood samples and oximeter readings were
analyzed in the 23 subjects. For each paired blood draw, the
weighted value of arterial and venous saturation was used to
compute a bias by comparing this weighted saturation value
with the instrument reading. Table2 contains summaries of
this bias in terms of the mean bias, standard deviation of the

bias, SE, and root mean square (Arms) error values for specific
ranges of calculated weighted arterial and venous saturations.
The pooled Arms error, tallied from all 5 instruments, was 9.1%.
Over the entire range of oxygenation studied, the mean bias
SD (precision) and Arms errors were: FORE-SIGHT 1.76 3.92
and 4.28; INVOS 0.05 9.72 and 9.69; NIRO-200NX 1.13
9.64 and 9.68; EQUANOX 3-wavelength 2.48 8.12 and 8.47;
EQUANOX 4-wavelength 2.84 6.27 and 6.86.
Plots of cerebral oximeter bias versus the hemoximetermeasured weighted value for rSo2 are presented in Figure1.

Table 2.Reading Bias of 5 Cerebral Oximeters

Range (%)

3050

5070

7090

3090

134
2.74
3.18
3.55 to 9.03
12.58
4.19

37
2.33
3.81
10.02 to 5.37
15.39
4.42

179
1.76
3.92
5.95 to 9.48
15.43
4.28

3050

5070

7090

3090

16
3.20
8.78
20.40 to 14.01
34.42
9.08

136
1.25b
9.38
17.45 to 19.95
37.40
9.43

29
3.75b
10.66
27.77 to 20.27
48.04
11.13

181
0.05
9.72
19.32 to 19.42
38.74
9.69

3050

5070

7090

3090

10
1.08
9.17
16.90 to 19.06
35.96
8.77

129
0.62
9.01
17.34 to 18.59
35.93
9.00

40
7.33
9.35
26.28 to 11.62
37.91
11.79

179
1.13
9.64
20.30 to 18.04
38.33
9.68

3050

5070

7090

3090

7
7.74
3.55
0.7714.71
13.93
8.41

133
3.63
6.62
9.58 to 16.83
26.41
7.53

35
2.93
11.12
25.43 to 19.58
45.01
11.34

175
2.48
8.12
13.67 to 18.63
32.30
8.47

3050

5070

7090

3090

6
0.13
7.46
14.49 to 14.75
29.24
6.81

137
3.34b
6.31
9.20 to 15.88
25.08
7.12

33
1.25b
5.63
10.15 to 12.66
22.82
5.68

176
2.84
6.27
9.58 to 15.26
24.84
6.86

FORE-SIGHT bias (Sco2 (0.3 Sao2 + 0.7 Svo2))

n
8
4.26
Mean biasa
Standard deviation
3.08
Limits of agreement
1.78 to 10.30
Interval
12.08
5.15
Arms
INVOS 5100C bias (Sco2 (0.25 Sao2 + 0.75 Svo2))
Weighted Sao2/Svo2
Range (%)
n
Mean bias
Standard deviation
Limits of agreement
Interval
Arms

NIRO-200NX bias (Sco2 (0.3 Sao2+ 0.7 Svo2))

Weighted Sao2/Svo2
Range (%)
n
Mean biasa
Standard deviation
Limits of agreement
Interval
Arms

EQUANOX 7600 3-wave bias (Sco2 (0.3 Sao2+ 0.7 Svo2))

Weighted Sao2/Svo2
Range (%)
n
Mean biasa
Standard deviation
Limits of agreement
Interval
Arms

EQUANOX 7600 4-wave bias (Sco2 (0.3 Sao2+ 0.7 Svo2))

Weighted Sao2/Svo2
Range (%)
n
Mean bias
Standard deviation
Limits of agreement
Interval
Arms

Bias was calculated as the difference between cerebral oximeter reading (Sco2) and the manufacturer-specified weighted arterial (Sao2) and jugular bulb (Svo2)
saturation.
Weighted Sao2/Svo2: weighting for jugular venous blood to arterial blood mixture is 75%/25% for the INVOS instrument and 70%/30 for the others.
Analysis of variance with repeated-measures and Tukey-Kramer honest significant difference used for multiple comparisons.
Arms = root mean square error; Sco2 = cerebral oximeter reading; Sao2 = arterial oxygen saturation; Svo2 = cerebral mixed venous hemoglobin saturation; interval =
upperlower limit of agreement.
a
All means in the row are different, P < 0.05.
b
Indicates pairs of means that are different statistically, P < 0.05.

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Cerebral Oximetry Performance During Hypoxia

Figure 2. Bias of 5 cerebral oximeters

plotted against difference between arterial and jugular bulb oxygen saturation.
Panels A to D show the bias of individual
data points (difference between cerebral
oximeter reading [Sco2] and weighted average of arterial and cerebral mixed venous
blood [Sa/vo2]) for the EQUANOX 3- and
4-wavelength models, the FORE-SIGHT,
INVOS, and NIRO-200NX. Panel E contains the combined data from all instruments. These data encompass an arterial
saturation range of approximately 70%
to 100%, with normocapnia maintained
throughout. The 95% confidence intervals
(CIs) for the slope and the P value are also
given. LOA = limits of agreement; Sao2 =
arterial oxygen saturation; Svo2 = cerebral
mixed venous hemoglobin saturation.

The FORE-SIGHT, NIRO-200NX, and EQUANOX 3-wavelength had significantly greater bias at lower Sao2, i.e., the
slope of the bias plots for these 3 instruments was negative
(Fig. 1, P < 0.0001 for significance of slope in all 3 cases).
The difference in mean bias between the high and low ends
of the saturation was relatively large (Table 2), meaning
that we have rejected hypothesis 1 for these instruments.
For example, for the FORE-SIGHT, there was a difference
in bias of about 10% saturation between weighted blood
saturations of 85% and 50%; for the NIRO-200NX, the bias
difference over this range was 15%; and for the EQUANOX
7600 3-wavelength instrument, the bias difference was 11%.
To determine whether increasing positive bias of the
cerebral oximeters with hypoxemia is related to the assumption of venous/arterial blood volume weighting, we plotted bias against the difference between arterial and cerebral
mixed venous saturations (i.e., nonweighted saturation) in
Figure2. In these plots, the slopes of bias in the EQUANOX
3-wavelength (0.12; CI, 0.020.22), FORE-SIGHT (0.06; CI,
0.02 to 0.14), and NIRO-200NX (0.14; CI, 0.27 to 0.013)

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instruments do not depend on the nonweighted saturation,

i.e., the slopes are not statistically different from zero. This
suggests that factors intrinsic to the difference in venous
and arterial saturation (e.g., changes in cerebral blood flow
or cerebral metabolism) may contribute to the differences in
bias between the high and low end of the saturation spectrum in these 3 instruments (hypothesis 2).

Analysis of Interindividual Differences in

Cerebral Oximeter Bias

Substantial differences in cerebral oximeter readings among

individuals were also observed. Between-subject differences
account for 36% to 87% of the variation in data among the 5
cerebral oximeters. This was evident when inspecting the bias
values for individual subjects in the plots in Figure1, A to E.
For each instrument, regression lines of bias plots for individual subjects appeared to have negative slopes with respect
to the weighted A V difference, with either a positive or
negative bias offset. The negative slope of the bias plots (i.e.,
more positive bias with hypoxia) is based on increasing bias of
individual subjects response at low oxygen levels and not an

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Figure 3. Distribution of regression lines of bias values for individual subjects for a randomly chosen cerebral oximeter, the Nonin
EQUANOX 3-wavelength instrument. Each line, calculated by the
method of least squares, is the regression line of data from 1 of
the subjects. Sco2 = cerebral oximeter reading; Sa/vo2 = weighted
saturation of venous and arterial blood.

artifact of bias being grouped for individuals at the high and

low end of the saturation ranges. These patterns can be seen in
Figure3 in which we have plotted regression lines for individual subject bias values for a randomly chosen instrument (random number generator), the Nonin EQUANOX 3-wavelength
cerebral oximeter. The percentage of variation attributable to
between-subject variability was, for EQUANOX 3-wavelength
76%, EQUANOX 4-wavelength 61%, FORE-SIGHT 37%,
INVOS 87%, and NIRO 77%, with the remainder variation
due to differences in reading because of changing saturation.
In contract, in a recent study of standard pulse oximeter performance in our laboratory, the source of variability was nearly
equally divided between changes in saturation and betweensubjects effects (John Feiner, UCSF, 2012, unpublished data).
To understand some of the basis for the differences in
bias among individuals, we performed a multivariate
analysis to isolate several factors previously established
to influence pulse oximeter bias. First, we examined the
influence of skin pigmentation on cerebral oximeter bias
(hypothesis 3), since we found that darkly pigmented skin
causes a positive mean bias in pulse oximeter readings at
low saturation.17,20 In Table3 are shown the mean bias values according to type of cerebral oximeter and the skin pigmentation of the subject, and Figure4 contains mean bias

for 3 different ranges of weighted arterial-cerebral mixed

venous saturation segregated by skin color groups. While
it appeared that bias was quantitatively more negative in
darkly pigmented subjects in all instruments, the repeatedmeasures analysis only showed a statistically significant
difference in the FORE-SIGHT cerebral oximeter (Table3,
multivariate analysis of skin color by reference saturation,
adjusted P < 0.001). The differences in bias between light
and intermediate or darkly pigmented subjects indicated
that darker skin tends to make this oximeter read lower
than the weighted average of cerebral mixed venous and
arterial blood, i.e., the bias values are generally more negative in groups of subjects with intermediate or darkly pigmented skin. Forty-eight percent of the subjects were of
intermediate or dark skin pigmentation, and 52% were
Caucasian. Even though the distribution of bias was not
normal, and we did not account for unequal covariances,
the degree of statistical significance (P < 0.001) for the interaction term (skin pigment times reference saturation) made
a type 1 error (falsely concluding a significant effect of skin
pigment on bias) unlikely in this case.
We also examined the factor of gender on bias (hypothesis 5) in cerebral oximeter readings (Table 4). In a multivariate analysis, we found that gender significantly
affected the magnitude of the cerebral oximeter bias in the
INVOS instrument (Fig.5), setting P < 0.001. The interaction of bias and gender was also significant (P < 0.001)
in a multivariate analysis for all instruments except the
EQUANOX 4-wavelength (P = 0.007) and FORE-SIGHT
(P = 0.92, Table4).

Effects of Hypoxia on Arterial to Cerebral Mixed

Venous Saturation

In Figure6, we plotted the A V saturation difference versus the arterial saturation for 6 representative subjects. The
slope of this relationship was significant, P < 0.0001.

DISCUSSION
Cerebral Oximeter Performance

Five cerebral oximeters all detected decreases in cerebral blood oxyhemoglobin saturation during systemic
hypoxemia in 23 healthy volunteer subjects. Based on the
manufacturer-defined ratio of cerebral venous and cerebral arterial blood detected by each device, we calculated
the bias between the cerebral oximeter reading and the
weighted values of arterial and cerebral mixed venous

Table 3.Multivariate Analysis of Bias of 5 Cerebral Oximeters by 3 Categories of Skin Pigmentation

Device
FORE-SIGHT
INVOS 5100C
NIRO-200NX
EQUANOX 7600 3-wave
EQUANOX 7600 4-wave
Pooled

Light
2.2 3.6a (93)
0.6 10.9 (94)
1.5 10.4 (92)
2.2 8.4 (92)
2.7 6.8 (92)
1.0 8.6 (463)

Medium
1.8 3.8 (70)
3.3 6.8 (71)
0.6 8.8 (71)
3.9 8.0 (67)
3.5 6.0 (68)
2.3 7.1 (347)

Dark
1.2 5.1a (16)
10.1 4.2 (16)
1.8 9.2 (16)
1.5 5.3 (16)
1.2 3.3 (16)
2.7 6.8 (80)

All
1.8 3.9 (179)
0.1 9.7 (181)
1.1 9.6 (179)
2.5 8.1 (175)
2.8 6.3 (176)
1.2 8.0 (890)

Skin
P value
0.049
0.14
0.91
0.56
0.80
0.24

Reference
Sa/vo2
P value
<0.0001
0.016
<0.0001
<0.0001
0.12
<0.0001

Skin
reference
P value
0.0004
0.15
0.011
0.53
0.18
0.21

Data are mean SD (n).

The multivariate analysis was by a repeated-measures model accounting for subject differences and compensated for repeated measures and difference values
of the reference Sao2/Svo2.
Sao2 = arterial oxygen saturation; Svo2 = cerebral mixed venous hemoglobin saturation.
a
Different from each other, P < 0.05, Tukey Kramer honest significant difference used for multiple comparisons.

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Cerebral Oximetry Performance During Hypoxia

Figure 4. Bias of 5 cerebral oximeters

during hypoxia, sorted by skin pigmentation. Panels A to D show the mean and
standard deviation of the bias (difference
between cerebral oximeter reading [Sco2]
and weighted average of arterial and cerebral mixed venous blood) for the Nonin
EQUANOX 3- and 4-wavelength models,
the Casmed FORE-SIGHT, Somanetics
INVOS, and Hamamatsu NIRO-200NX
for 3 ranges of weighted arterial and jugular bulb saturation. The weighting of cerebral mixed venous and arterial blood was
assumed to be 75%/25% for the INVOS
instrument and 70%/30% for the others.
Panel E contains the combined data from
all instruments. The effect of skin pigment
on bias was only significant for the FORESIGHT instrument (P = 0.014). Statistics
for the univariate and multivariate analyses are given in Table 3.

saturation. As summarized in Table 2 and Figure 1, the

FORE-SIGHT, NIRO 200-NX, and EQUANOX 3-wavelength instruments have a significantly positive mean bias
during hypoxia. They indicate a cerebral saturation significantly higher than that based on simultaneous arterial and
cerebral mixed venous measurements, whereas the other
instruments have no significant mean bias. However, the
variability in baseline readings among the 5 instruments
was substantial, with significant between-subject and

between-instrument variation. This indicates that unlike

pulse oximeters, currently manufactured cerebral oximeters
do not provide an absolute measurement of oxyhemoglobin saturation in the tissue region of interest, despite the
theory that spatially resolved spectroscopy can determine
a scaled tissue hemoglobin concentration and therefore the
relative concentrations of oxy- and deoxyhemoglobin. The
between-subject variability and dynamic error of readings
makes it difficult to determine the absolute threshold of

Table 4.Multivariate Analysis of Bias of 5 Cerebral Oximeters by Gender

Device
FORE-SIGHT
INVOS 5100C
NIRO-200NX
EQUANOX 7600 3- wave
EQUANOX 7600 4- wave

Female
2.0 4.5 (70)
7.4 9.0 (71)
4.9 11.4 (70)
1.7 8.5 (68)
0.35 6.9 (68)

Male
1.6 3.5 (109)
4.8 6.8 (110)
1.3 7.4 (109)
5.1 6.6 (107)
4.4 5.3 (108)

All
1.8 3.9 (179)
0.1 9.7 (181)
1.1 9.6 (179)
2.5 8.1 (175)
2.4 6.3 (176)

Gender
P value
0.61
0.0007
0.051
0.021
0.038

Reference Sa/vo2
P value
0.0002
0.02
<0.0001
<0001
0.25

Gender reference
P value
0.92
0.0003
<0.0001
0.0002
0.007

The multivariate analysis was by a repeated-measures model accounting for subject differences and compensated for repeated measures and difference values
of the reference Sao2/Svo2.
Sao2 = arterial oxygen saturation; Svo2 = cerebral mixed venous hemoglobin saturation.

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Figure 5. Bias of 5 cerebral oximeters during hypoxia, sorted by gender. Panels A

to D show the mean and standard deviation of the bias (difference between cerebral oximeter reading [Sco2] and weighted
average of arterial and cerebral mixed
venous blood) for the Nonin EQUANOX
3- and 4-wavelength models, the Casmed
FORE-SIGHT, Somanetics INVOS, and
Hamamatsu NIRO-200NX for 3 ranges
of weighted arterial and jugular bulb saturation. The weighting of cerebral mixed
venous and arterial blood was assumed to
be 75%/25% for the INVOS instrument and
70%/30% for the others. Panel E contains
the combined data from all instruments.
Statistics for the multivariate analysis of
gender and bias are given in Table 4.

saturation that results in tissue damage. This is currently

an important disadvantage of noninvasive optical brain
oximetry. Until the factors that contribute to the variability

are better understood, the utility of cerebral oximetry will

remain limited. This is essentially the same conclusion
made by Henson et al.21 in 1998 after a study of the INVOS
3100 cerebral oximeter (Somanetics Corp). Henson et al.21
found that while the INVOS 3100 was capable of detecting
changes in oxygenation, the relationship between instrument reading and hypoxia exhibited a variety of slopes and
intercepts between different individuals, not unlike the plot
in Figure3.

Causes of Cerebral Oximeter Bias

Figure 6. Plot of the difference between arterial and jugular bulb

saturation versus arterial saturation for 6 representative subjects.
Sao2 = arterial oxygen saturation; Svo2 = cerebral mixed venous
hemoglobin saturation.

October 2013 Volume 117 Number 4

Manufacturers of cerebral oximeters have apparently

used simultaneous measurements of arterial and cerebral
mixed venous saturation to create algorithms for cerebral
oximeter output, similar to our protocol. This process
pools data from individuals with different ratios of arterial and venous blood but assumes a fixed ratio of 70/30
or 75/25 venous to arterial blood volume. The 70/30
ratio of venous to arterial blood is based on measurements of brain arterial and venous blood volumes with
positron emission tomography.22,23 This assumption, and

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Cerebral Oximetry Performance During Hypoxia

measurements of saturation in venous and arterial blood

samples, can be used to calibrate an instrument to produce an output that is sensitive to desaturation (as was
found, all 5 oximeters are good at detecting decreases in
rSo2 during isocapnic hypoxia), but will not address the
differences in arterial/venous mixtures among individuals. This could be the fundamental reason that the Arms
of cerebral oximeters is so much greater than with pulse
oximetry (9% vs 2%3%). Unlike pulse oximeters, cerebral oximeters have no method similar to relating saturation to the ratio of light absorbance by pulsatile and
nonpulsatile signals, so they cannot easily cancel out
interfering light absorption. For cerebral oximeters, contributions to systematic bias, such as skin pigmentation
or gender (Tables3 and 4 and Figs.4 and 5), will similarly
not be corrected by simply averaging data from a broad
population of subjects; this approach is appropriate for
calibrating the average effects of desaturation but not for
reducing bias among individuals. Manufacturers may
also use other signal processing and interference correction algorithms to improve performance, but it is unclear
how these relate to differences in performance among the
5 cerebral oximeters.
When we plotted the bias between Sco2 and Sa/vo2
against the difference in arterial and venous saturation, we
found that a greater bias at low saturation was eliminated
in the instruments showing this bias (Fig.2). This suggests
that differences in the ratio of venous to arterial blood volumes in different subjects accounts for at least some of the
more positive bias at low saturation in these instruments,
assuming that oxygen consumption of the brain remains
the same and that the equation rSo2 = (Sao2) + (1 )Svo2
applies where is the fraction of arterial to venous blood
volume in the brain tissue illuminated by the oximeter.
Thus, changes in arterial and venous blood volume would
produce changes in cerebral oximeter bias during maneuvers that change this ratio, including changes in cerebral
blood flow produced by hypoxemia, hypercapnia or hypocapnia, changes in posture, venous outflow obstruction, etc.
However, this was apparently not the case in the Kim et al.16
study where changes in CO2 did not change bias, although
the bias plots in the Kim et al.24 study compare cerebral
oximeter readings with only the average of jugular venous
and radial arterial saturation and not the weighted average
of venous and arterial as would be evaluated by the cerebral oximeter. Isocapnic hypoxia increases cerebral arterial
blood flow in humans, probably causing increases in arterial blood volume relative to venous volume in the frontal
cortex. Figure6 shows that the A V saturation difference
decreased during hypoxia in all our subjects. For cerebral
oxygen delivery to be constant, arterial blood flow must
increase. This almost certainly means that arterial volume
increases to some degree during hypoxia, violating the constant A V volume assumption.
Using positron emission tomography techniques, and
reviewing data from several types of experimental studies
in humans and experimental animals, Ito et al.22,23 concluded
that changes in CO2 produce changes in arterial blood volume and not venous volume. Although we maintained normocapnia throughout our studies, we expect that arterial
blood volume would increase with the cerebral vasodilation

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produced by hypoxemia. Accordingly, the ratio of venous to

arterial blood volume probably changes during the course
of our experiments (unlike the case for hypo- and hypercapnia, we are unable to locate studies measuring relative
cerebral venous and arterial blood volumes during isocapnic hypoxia). If this assumption is true, then the amount
of arterial blood seen by the cerebral oximeter would
increase during hypoxia, producing an overestimation of
true rSo2. This type of error causes a positive bias in cerebral
oximeter readings at low saturation, as was seen to varying
degrees in the instruments tested. The effect was minimal
in the 4-wavelength instrument from Nonin and the INVOS
5100C, but significant for the Casmed, Hamamatsu, and
3-wavelength Nonin instruments.

Clinical Implications of Cerebral Oximeter

Performance

Cerebral oximetry tracks changes in saturation better than

absolute saturation, and pulse hemoglobinometry tracks
changes in hemoglobin better than absolute hemoglobin.25
Both methods have large interindividual differences. This
is a major barrier to wider adoption of this and similar
technologies.
The apparently significant influence of venous to arterial
blood ratios on cerebral oximeter bias has implications for
interpreting cerebral oximeter readings in clinical states that
involve changes in the ratio of venous and arterial blood in
the sensor field. These conditions include changes in intracranial pressure, venous outflow obstruction, use of vasoactive drugs and anesthetics, and alterations in body position.
Studying how these alterations influence cerebral oximeter
readings could lead to improvements in cerebral oximeter
performance.
In practical terms, the interindividual differences in saturation are a major limitation of present cerebral oximetry
technology because it is difficult to set a threshold for a
dangerous lower level for Sco2. If readings among individuals vary by 20%, how can a threshold for concern be established? At present, the trend in values in an individual may
be more useful and indicative of brain well-being than an
absolute value, although the different slopes of individual
subjects on the bias plots make this aspect of cerebral oximetry problematic as well.
Similar to previous studies involving finger pulse
oximeters, skin pigmentation and gender were related to
bias for some instruments.17,20 In the case of darkly pigmented skin, more negative bias was observed (although
was statistically significant only for FORE-SIGHT); this is
the opposite of the effect in pulse oximetry where darkly
pigmented skin produced higher pulse oximeter readings at low saturation. Since the direction was the same
in all the devices, given the few data points in darkly
pigmented individuals, our data may not have been sufficiently powered to detect differences. Nonetheless, we
speculate that more darkly pigmented skin is seen by
the cerebral oximeter as more venous, biasing the reading
toward lower saturation values. In the case of gender, all
instruments except FORE-SIGHT read lower in women,
across the spectrum of saturations. Whether this is related
to lower hemoglobin, thinner cranial bone, or other factors
in female subjects is not clear.

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Study Limitations

Because our study involved only a small number of very

darkly pigmented subjects, our study has limited power to
conclude that dark skin creates cerebral oximeter reading
errors. Another limitation is that all subjects were studied in
a 30 head-up position and this might cause bias compared
with supine position. Another source of error may have
been introduced by the position of different sensor types
next to each other in the same subject (i.e., right and left
sides). It is possible that even with shielding, light interference might occur, but since location and type of neighboring
sensor were randomized, this should have had a minimal
effect on our overall conclusions.

Conclusions

Five commercially available cerebral oximeters tracked

changes in cerebral blood oxygenation during hypoxia
in healthy volunteers. However, significant imprecision
between weighted arterial-cerebral mixed venous saturation
and cerebral oximeter readings were found, with an average
RMS error of 9.1%. Differences in skin pigment, gender, and
the assumed mixture of arterial and cerebral venous blood in
the detection field likely contribute significantly to the bias
and imprecision in readings from these devices. E
DISCLOSURES

Name: Philip E. Bickler, MD, PhD.

Contribution: This author designed and conducted the study
and prepared the manuscript.
Attestation: Philip Bickler approved the final manuscript,
attests to the integrity of the original data and the analysis
reported in this manuscript, and is the archival author.
Name: John R. Feiner, MD.
Contribution: This author designed and conducted the study
and prepared the manuscript.
Attestation: John Feiner approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
Name: Mark D. Rollins, MD, PhD.
Contribution: This author helped conduct the study and edited
the manuscript.
Attestation: Mark Rollins approved the final manuscript and
attests to the integrity of the original data and the analysis
reported in this manuscript.
This manuscript was handled by: Dwayne R. Westenskow, PhD.
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