Pediatr Blood Cancer 2012;59:881–887
Cerebral Tissue Hemoglobin Saturation in Children With Sickle Cell Disease
Charles T. Quinn, MD, MS1* and Michael M. Dowling, MD, PhD, MSCS2
Peripheral hemoglobin (Hb) desaturation is a common finding
in sickle cell disease (SCD) that is associated with abnormally
increased cerebral arterial blood flow velocities and central ner-
vous system complications such as overt stroke [1–4]. Hb desatu-
ration in SCD is the product of a combination of several known
and suspected factors, including a compensatory rightward shift
of the oxy-hemoglobin dissociation curve due to chronic anemia,
physiochemical properties of sickle Hb in solution, ventilation-
perfusion mismatching, possible cardiopulmonary shunts, and the
confounding presence of dyshemoglobins [5–7]. Although a caus-
al link has not been established, Hb desaturation might predispose
to stroke by decreasing arterial oxygen content and limiting bulk
delivery of oxygen to the brain, especially given SCD patients’
chronic moderate to severe anemia, cerebral arterial stenosis,
decreased cerebrovascular reserve, altered oxygen extraction,
and periodic acute anemic or hypoxemic events [8–11].
Cerebral oximetry is a non-invasive, near-infrared spectroscop-
ic technique to measure Hb saturation in the brain. Cerebral
oximetry measurements have been reported in patients with
SCD previously [12–15]. However, these studies used an early-
generation oximeter that did not measure the actual or absolute
value of cerebral Hb saturation. Rather, it provided a relative
value that helps to monitor changes in regional cerebral Hb
saturations (rSO2) from a known baseline state (e.g., following
induction of anesthesia). This trending oximeter is also suscepti-
ble to interference by dark skin pigmentation because it uses only
two wavelengths [16,17]. These early data suggested that cerebral
Hb saturation is decreased in patients with SCD, but surprisingly
no associations between peripheral and cerebral Hb saturation
were found across studies [12–15].
We wished to determine whether peripheral Hb desaturation is
associated with Hb desaturation in the brain, because this could
provide a mechanistic link between peripheral Hb desaturation
and stroke. Therefore, we used a new-generation cerebral oxime-
ter that measures the actual or absolute Hb oxygen saturation in
cerebral tissue (SCTO2). By using four wavelengths, this oximeter
is insensitive to interference by dark skin pigmentation [16,17].
We hypothesized that SCTO2 was highly correlated with
peripheral Hb oxygen saturation as measured by simultaneous
pulse oximetry (SPO2). We also explored the relationships
between SCTO2and clinical, laboratory, and neurophysiological
characteristics as well as the response to transfusion.
DESIGN AND METHODS
Study Overview and Participants
We performed a cross-sectional study of the Dallas Newborn
Cohort (DNC) [18,19] to describe the distribution of SCTO2in
children with SCD and to test the primary hypothesis that SCTO2
correlated with SPO2. We studied all forms of SCD, including
sickle cell anemia (HbSS), and sickle-b0-thalassaemia (HbSb0),
sickle-hemoglobin C disease (HbSC) and sickle-bþ-thalassemia
(HbSbþ). Participants with HbSS and Hb Sb0were analyzed as a
single group (HbSS/Sb0), as were those with Hb SC and Hb Sbþ
(HbSC/Sbþ). Chronic transfusions were an exclusion from the
main study. Response to single, simple transfusions was observed
in a separate group of 10 chronically transfused participants. The
local institutional review board approved this study. Parents or
legal guardians of minors provided written informed consent.
Minors ?10 years of age also provided assent.
Background. Desaturation of hemoglobin (Hb) in cerebral tis-
sue, a physiologic marker of brain vulnerable to ischemic injury,
can be detected non-invasively by transcranial oximetry. Absolute
cerebral oximetry has not been studied in sickle cell disease (SCD),
a group at very high risk of cerebral infarction in whom prevention
of brain injury is key. Procedure. We measured absolute Hb satu-
ration in cerebral tissue (SCTO2) in children with SCD using near-
infrared spectrophotometry and investigated the contributions of
peripheral Hb saturation (SPO2), hematologic measures, cerebral
to SCTO2. We also assessed the effects of transfusion. Results.
We studied 149 children with SCD (112 HbSS/Sb0; 37 HbSC/
Sbþ). SCTO2was abnormally low in 75% of HbSS/Sb0and 35%
of HbSC/Sbþpatients. SCTO2 (mean ? SD) was 53.2 ? 14.2 in
HbSS/Sb0and 66.1 ? 9.2% in SC/Sbþpatients. SCTO2correlated
with age, sex, Hb concentration, reticulocytes, Hb F, and SPO2, but
not transcranial Doppler arterial blood flow velocities as continuous
measures. In multivariable models, SPO2, Hb concentration, and
age were significant independent determinants of SCTO2. Cerebral
vasculopathy was associated with ipsilateral cerebral desaturation.
Transfusion increased SCTO2and minimized the inter-hemispheric
differences in SCTO2due to vasculopathy. Conclusions. Cerebral
desaturation, a physiologic marker of at-risk brain, is common in
SCD, more severe in HbSS/Sb0patients, and associated with pe-
ripheral desaturation, more severe anemia, and increasing age.
Cerebral oximetry has the potential to improve the identification
of children with SCD at highest risk of neurologic injury and
possibly serve as a physiologic guide for neuroprotective therapy.
Pediatr Blood Cancer 2012;59:881–887.
? 2012 Wiley Periodicals, Inc.
brain; desaturation; hypoxemia; risk factor; sickle cell disease; stroke
Additional Supporting Information may be found in the online version
of this article.
1Division of Hematology, Cincinnati Children’s Hospital Medical
Center, Cincinnati, Ohio;
U.T. Southwestern Medical Center at Dallas, Dallas, Texas
2Division of Pediatrics and Neurology,
Grant sponsor: National Institutes of Health; Grant number: KL2-
RR024983; Grant sponsor: First American Real Estate Services, Inc..
Authorship: C.T.Q. and M.M.D. designed the study, analyzed the
data, and wrote the manuscript.
Conflict of interest: Nothing to declare.
*Correspondence to: Charles T. Quinn, MD, MS, Cincinnati
Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati,
OH 45220. E-mail: email@example.com
Received 13 December 2011; Accepted 16 May 2012
? 2012 Wiley Periodicals, Inc.
Published online 7 June 2012 in Wiley Online Library
We used the FORE-SIGHT1cerebral oximeter (CAS Medical
Systems, Inc., Branford, CT) to measure SCTO2with bi-frontal
probes. SCTO2is measured mainly in gray matter (near the gray-
white junction) in the frontal lobes, providing separate readings
for each hemisphere. The probe overlays the watershed zone
between the anterior and middle cerebral arteries. SCTO2is a
measurement of a mix of arterial (?30%) and venous (?70%)
blood , reflecting the balance between cerebral tissue oxygen
supply and demand. The normal range of SCTO2values in normal,
normoxic individuals breathing room air is approximately 60–
We used the Nellcor N-395 pulse oximeter (Nellcor Puritan
Bennett Inc., Pleasanton, CA) to measure SPO2. For the main
study, we obtained single or ‘‘spot’’ measurements of cerebral
tissue Hb saturation (SCTO2) and peripheral Hb saturation
(SPO2) during steady-state (‘‘well’’) clinic visits. In a separate
analysis, intermittent or continuous SCTO2monitoring was per-
formed in 10 participants who received a simple transfusion as
part of a chronic transfusion program for primary or secondary
stroke prophylaxis. All transfused packed red blood cells were
stored for 7 or fewer days before transfusion. All measurements
of SCTO2and SPO2were taken during the day in participants who
were awake and breathing room air.
Clinical Imaging and Laboratory Studies
Transcranial Doppler ultrasonography (TCD) examinations
were performed as part of an institutional screening program.
We chose the TCD closest to the time of cerebral oximetry for
analysis. TCD examinations were performed according to the
stroke prevention in sickle cell anemia (STOP) study protocol
 by a STOP-certified technician using a non-imaging system
(2-Mhz pulsed Doppler ultrasonograph, model TC8080; Nicolet
Viasys Healthcare, Madison, WI). We collected the time-averaged
maximum mean velocities (TAMMV) in the right and left middle
cerebral arteries (RMCA, LMCA), the right and left anterior
cerebral arteries (RACA, LACA), the right and left distal internal
carotid arteries (RdICA, LdICA), and the vertebrobasilar system
(VB). We used the highest TAMMV in each artery for analysis,
consistent with clinical care, and the MCA:VB and ACA:VB
ratios as a proxies for degree of stenosis . The following
laboratory studies were obtained during steady-state clinic visits:
complete blood count, percent reticulocytes, and percent fetal Hb
(Hb F). If not performed on the same day as the oximetry, we
chose the values closest in time for analysis.
Sample Size and Statistical Analysis
We first validated the normal range of SCTO2in a convenience
sample of children without SCD or anemia, selecting the upper
and lower limits to include at least 2 standard deviations (SD)
above and below the mean. The control subjects were not race-
matched because the cerebral oximeter we used is insensitive to
interference by dark skin pigmentation, and racial differences
in SCTO2have not been reported [16,17,21,22].
The sample size for the main study was estimated in advance
to detect a minimum correlation of 0.25 (r) between SCTO2
and SPO2 (a ¼ 0.05; 1 S b ¼ 0.8) in the HbSS/Sb0group.
Pediatr Blood Cancer DOI 10.1002/pbc
Summary statistics were calculated for variables of interest.
Differences between groups were tested by the Mann–Whitney
U or Kruskal–Wallis tests, where appropriate, and paired data by
the Wilcoxon matched-pairs signed rank test. We used Spearman
correlation to test the two pre-specified primary hypotheses that
both right- and left-sided SCTO2directly correlated with SPO2.
Spearman correlation was also used to test for monotonic
relationships between SCTO2and these pre-specified independent
variables: age, sex, genotype, Hb concentration, percent Hb F,
percent reticulocytes, TAMMV in all interrogated vessels,
MCA:VB, and ACA:VB. We performed multivariable linear
regression of SCTO2 in the HbSS/Sb0group only, because of
the small size of the HbSC/Sbþgroup. We chose independent
variables for inclusion in multivariable models, one model for
each hemisphere, if bivariate correlation with SCTO2(the depen-
dent variable) was significant at a conventional P < 0.20 level.
From these, we built the final models using independent variables
that were significant at P < 0.05 by forced entry. Sex was coded
by an indicator variable. We then used binary logistic regression
to model the odds of a low SCTO2defined as a value less than the
25th percentile for the study population using the independent
variables from the final multiple linear regression models. For
all models we performed appropriate diagnostics to ensure that
assumptions were met.
Individuals could participate only once in this study, but each
provided a right- and left-sided value of SCTO2. Subjects with
missing measurements were excluded from each analysis; no data
were imputed. For the two pre-specified primary hypothesis tests,
we considered P < 0.025 to be statistically significant. Other
statistical hypothesis tests were considered exploratory, for which
we considered P < 0.05 to be nominally significant. We used
G?Power version 3.1 for Mac to calculate sample size ,
SPSS version 19 statistical software for Mac (IBM Corp., Somers,
NY) to analyze the data, and Prism 5.0d for Mac (GraphPad
Software, Inc., La Jolla, CA) to generate figures.
Validation of Normal Range of SCTO2
We validated the reported normal range of SCTO2(60–85%) in
29 children without blood disorders (e.g., healthy siblings of
patients or children in remission and off therapy for leukemia;
N ¼ 17) or with a non-anemic blood disorder verified by concur-
rent hemoglobin measurement (e.g., hemophilia or neutropenia;
N ¼ 12). The mean SCTO2was 76.1% (median 76.4, range 68–
90.8, standard deviation 4.8, mean ? 2 SD 66.8–86.0). Thus, we
used a reference range of 65–90% for SCTO2in healthy children
for this study.
Characteristics of Participants With SCD
We studied 149 participants with a mean age of 6.6 years (SD
4.7, median 5.5). Almost all were African-American (98.3%); two
(1.7%) were Caucasian. Table I provides characteristics by
genotype group (HbSS/Sb0, N ¼ 112; HbSC/Sbþ, N ¼ 37).
Twenty-two participants were taking (prescribed) hydroxyurea
at the time of oximetry (21 HbSS, 1 HbSC). We separately
evaluated an additional ten participants with HbSS who were
receiving chronic transfusions for secondary stroke prophylaxis
(mean age 11.2 years, 50% male).
882Quinn and Dowling
Distribution of SCTO2
The distribution of SCTO2was skewed to the left (lower) for
both genotype groups in both hemispheres, and approximately
35% and 75% of HbSC/Sbþ
respectively, had values below the lower limit of normal that
we validated (Fig. 1 A,B). SCTO2was significantly lower in the
HbSS/Sb0group than the HbSC/Sbþgroup for both hemispheres
(right SCTO2: median 54.3 vs. 66, P < 0.001; left SCTO2: median
52.3 vs. 64.7, P < 0.001; Fig. 1C). For the HbSS/Sb0
group, SCTO2decreased with increasing age group (P < 0.001;
Fig. 2). The trend for SCTO2decreasing with age in the HbSC/
Sbþgroup was not statistically significant (data not shown). We
then compared the SCTO2of the HbSS/Sb0group to a separate
group of patients with other forms of anemia (other than SCD)
and found that the SCD group had lower SCTO2than the non-SCD
group even after adjusting for the difference in Hb concentration
between groups (52.1% vs. 62.2%; P ¼ 0.023; Supplemental
Correlates of SCTO2
Table II shows the bivariate correlations between SCTO2and
the pre-specified clinical and laboratory variables by genotype
group. Consistent with our pre-specified primary hypotheses,
sided SCTO2 (r ¼ 0.32, P < 0.001) were directly correlated
with SPO2 in the HbSS/Sb0group (Fig. 3). Also directly
(positively) correlated with SCTO2were Hb concentration, percent
HbF, and sex. Age and percent reticulocytes were inversely
correlated with SCTO2. For the smaller HbSC/Sbþgroup,
correlations between SCTO2and the pre-specified variables were
weak or absent (Table II). SCTO2did not correlate with TAMMV
in any ipsilateral vessel, the MCA:VB, or ACA:VB in either
genotype group (data not shown).
(r ¼ 0.40,P < 0.001)andleft-
Multivariable Modeling of SCTO2
We found a significant linear relationship between SCTO2
(right- and left-sided) and SPO2, Hb concentration, and age
(Table III). As expected, lower SPO2and Hb concentration were
associated with lower SCTO2. Higher age was associated with
lower SCTO2. Female sex, encoded as a binary indicator variable,
was associated with higher SCTO2for right-sided SCTO2only.
Percent reticulocytes and percent Hb F did not have a significant
linear relationship with SCTO2 when controlling for the other
variables. These multivariable models explained a little less
than half of the variability in SCTO2, while SPO2alone explained
only 5–10% of the variability in SCTO2.
We then modeled the odds of having a value of SCTO2that was
less than the 25 percentile in the study population (45% on the
right and 40.5% on the left) using binary logistic regression.
Simultaneously controlling for Hb concentration, age and sex
(right only), each unit decrease in SPO2 gave an odds of 1.5
(95% CI: 1.004–1.8) and 1.4 (95% CI: 1.05–1.9) for a
low SCTO2in the right and left hemispheres, respectively. The
area under the receiver-operating characteristic curves for both
models was 0.84 (P < 0.001).
Relationship of SCTO2to TCD Abnormalities
The median time between TCD and SCTO2measurements was
172.5 days. SCTO2was not correlated to TAMMV in any vessel
when TAMMV was considered as a continuous measurement
(HbSS/Sb0; N ¼ 70; Supplemental Fig. 2). Two tentative rela-
tionships were seen when TAMMVs were grouped by STOP
TABLE I. Characteristics of Participants by Genotype Group
HbSS/Sb0(N ¼ 112),
HbSC/Sbþ(N ¼ 37),
aPresented as the ratio of the number of males to females.
(panel B) hemispheres, respectively, for the entire study population. Participants with sickle cell anemia and sickle-b0-thalassaemia (HbSS/
Sb0) are differentiated from those with sickle-hemoglobin C disease and sickle-bþ-thalassemia (HbSC/Sbþ). Participants with HbSS/Sb0had
lower SCTO2than HbSC/Sbþparticipants in both hemispheres (panel C). Box-plots depict Tukey’s hinges (box: 25–75th percentiles with
median; whiskers: 1.5 times the interquartile range) and outliers. Dotted lines indicate the upper (90%) and lower (65%) limits of SCTO2for
Distribution of cerebral tissue hemoglobin saturation (SCTO2) by genotype group. Histograms of SCTO2by right (panel A) and left
Cerebral Desaturation in Sickle Cell Disease883
Pediatr Blood Cancer DOI 10.1002/pbc
categories in exploratory analyses. First, right-sided SCTO2was
lower when there were abnormal or conditional TAMMVs in
sided SCTO2was numerically lower when there were abnormal
TAMMVs in ipsilateral dICA (Supplemental Fig. 2).
Response to Transfusion
Ten participants with SCD who were chronically transfused
continuous SCTO2 monitoring during a simple transfusion.
SCTO2 increased after transfusion, significantly on the left
(Fig. 4). Twenty percent (2/10) of SCTO2 measurements were
normal (?65%) before transfusion, increasing to 40% and 50%
normal on the left and right, respectively, after transfusion. Two of
these participants had known severe unilateral cerebral vasculop-
athy, demonstrated by magnetic resonance angiography, and had
continuous SCTO2 monitoring during a transfusion (Fig. 5).
Patient 1 had severe stenosis of the left internal carotid artery,
and Patient 2 had a completely occluded right internal carotid
artery. Both participants had a lower pre-transfusion SCTO2on the
side of the stenosis or occlusion. The right-left difference
in SCTO2was 5% (absolute) and for Patient 1 and 20% (absolute)
for Patient 2. The SCTO2rose during the course of transfusion
(10–30% absolute rise in SCTO2), and by the end of the
transfusion the right- and left-sided saturations appeared to
In this largest study of cerebral oximetry in children with SCD
to date, and the only report of absolute cerebral oximetry in this
population, we find that cerebral Hb desaturation is a common
and sometimes severe neurophysiologic abnormality, especially in
HbSS/Sb0patients. We confirmed our primary, pre-specified hy-
pothesis that cerebral desaturation is directly correlated with pe-
ripheral Hb desaturation and further showed that cerebral
desaturation (decreased SCTO2) is associated with lower Hb con-
centration and increasing age. Our findings are consistent with the
important prior observation that a lower Hb concentration is as-
sociated with a higher risk of overt stroke . Males also had
lower cerebral saturation than females, consistent with the prior
observation that males with SCD have a lower peripheral Hb
saturation than females . We also found evidence that cerebral
vasculopathy is associated with ipsilateral cerebral desaturation
and that transfusion improves cerebral saturation.
There are four previous reports of cerebral oximetry in SCD
[12–15], all of which used early-generation oximeters (INVOS1
1400 or 5100, Somanetics Corp., Troy, MI) that do not measure
the absolute or actual value of SCTO2. Instead, these INVOS
devices report a relative value of regional brain saturation (called
rSO2), which is not the actual saturation, whose purpose is to
monitor changes or trends in cerebral saturation from a known
baseline state (e.g., following the induction of anesthesia). These
prior studies showed that cerebral Hb saturation is decreased in
participants with sickle cell anemia and sickle-b0-thalassaemia (HbSS/Sb0) in the right (panel A) and left (panel B) hemispheres, respectively.
Box-plots depict Tukey’s hinges (box: 25–75th percentiles with median; whiskers: 1.5 times the interquartile range) and outliers. Dotted lines
indicate the upper (90%) and lower (65%) limits of SCTO2for healthy children.
Cerebral tissue hemoglobin saturation (SCTO2) decreases with age. Distribution of SCTO2by age groups of uniform width in
TABLE II. Spearman Rank Correlations Between SCTO2and Clinical and Laboratory Variables by Genotype Group
HbSS/Sb0(N ¼ 102)HbSC/Sbþ(N ¼ 37)
aMale coded as 0, female coded as 1.
884Quinn and Dowling
Pediatr Blood Cancer DOI 10.1002/pbc
patients with SCD, but no associations between rSO2and SPO2or
Hb concentration were identified. The relationship between cere-
bral artery blood flow velocity measured by TCD and SCTO2was
not assessed in these prior studies. By measuring the absolute or
actual saturation in cerebral tissue (SCTO2) in this study using the
CASMED FORE-SIGHT oximeter (CAS Medical Systems, Inc.,
Branford, CT), we clearly show that cerebral Hb saturation is
related to both peripheral Hb saturation (directly) and Hb concen-
tration (inversely). Perhaps these relationships were not discerned
in previous investigations [12–15] because an arbitrary value for
cerebral saturation was used (rSO2, not absolute SCTO2), which
may have been too inaccurate to resolve the relatively small
overall contributions of Hb concentration and SPO2to cerebral
saturation that we found.
Given the findings of this study and our past related studies
[3,4], we suggest that Hb desaturation predisposes to stroke and
other neurologic morbidity by limiting bulk delivery of oxygen to
the brain. Arterial oxygen content comprises mainly oxygen
bound to Hb as well as a small component of dissolved oxygen
[(Hb ? 1.36 ? SAO2) þ (0.0031 ? PAO2)]. This is significant,
because both Hb and SAO2, the main determinants of oxygen
content, are often low in SCD. Desaturation in SCD is partly
the result of a compensatory rightward shift of the oxy-hemoglo-
bin dissociation curve due to chronic anemia, which serves to
preserve oxygen delivery in normal physiologic conditions. How-
ever, this shift may be insufficiently protective in SCD, in which
there may be severe anemia, cerebral arterial stenosis, decreased
cerebrovascular reserve, altered oxygen extraction, and periodic
acute anemic or hypoxemic events [8–11] The lower SCTO2in
SCD patients compared to anemic patients without SCD, even
after adjustment for degree of anemia, suggests that something
about SCD, in addition to the anemia, also accounts for the
desaturation (e.g., vasculopathy, microvascular vaso-occlusion, dis-
ordered cerebral autoregulation, and/or altered Hb oxygen affinity).
Given that cerebral Hb saturation has limited associations with
TCD findings and is only partially explained by peripheral satu-
ration, measurements of SCTO2provide additional, new informa-
tion that is not provided by TCD or pulse oximetry. SCTO2is a
measurement of a mixture of cerebral arterial (30%) and venous
(70%) blood. Decreased SCTO2, therefore, is the result not only of
arterial desaturation, as reflected by pulse oximetry, but also a
larger component of venous desaturation due to cerebral oxygen
extraction. Decreased SCTO2indicates a marginal blood supply to
regions of the brain as well as a higher risk of intravascular
sickling from deoxygenation in the brain. Because SCTO2reflects
the balance between cerebral tissue oxygen supply and demand, it
may be considered a physiologic biomarker for brain at risk of
ischemic injury. Cerebral Hb desaturation, which worsens with
age and severity of anemia, might also be a mechanistic link
between the decline in cognitive performance that has been ob-
served in older (adult) SCD patients with more severe anemia
between SPO2and SCTO2in the right (panel A) and left (panel B) hemispheres, respectively, for patients with sickle cell anemia and
sickle-b0-thalassaemia (HbSS/Sb0). Spearman r correlation coefficients are shown, and the lines depict the linear relationships between SPO2
Correlation between peripheral hemoglobin saturation (SPO2) and cerebral tissue hemoglobin saturation (SCTO2). Correlations
TABLE III. Multivariable Linear Regression Models of SCTO2in HbSS/Sb0Participants
Adjusted model r2¼ 0.46Adjusted model r2¼ 0.40
aSex encoded as a binary indicator variable.
Cerebral Desaturation in Sickle Cell Disease 885
Pediatr Blood Cancer DOI 10.1002/pbc
We propose that cerebral oximetry, a rapid and non-invasive
technique, might help to identify children with SCD at highest
risk of neurologic injury and, possibly, guide neuroprotective
therapy. For example, Figures 4 and 5 show that transfusion can
improve cerebral saturation and minimize inter-hemispheric
differences in cerebral saturation associated with unilateral
vasculopathy. As such, SCTO2 should be studied as a patient-
specific physiologic monitoring parameter for transfusion therapy.
respectively, before and after transfusion. SCTO2increased significantly after transfusion on the left. Median values are shown for each group
before and after transfusion. Dotted lines indicate the upper (90%) and lower (65%) limits of SCTO2for healthy children.
Effect of transfusion on cerebral tissue hemoglobin saturation (SCTO2). SCTO2in the right (panel A) and left (panel B) hemispheres,
the side of occlusive sickle cerebral vasculopathy, but transfusion minimizes the difference between the sides. The graph shows the changes
in SCTO2on the right (red) and left (blue) during the course of transfusion. Magnetic resonance angiography is shown for both patients. Patient
1 has severe stenosis of the left internal carotid artery (arrows), and Patient 2 has a completely occluded right internal carotid artery (arrows).
The reasons for the differences in the shapes of the curves between patients is not known, but the response to transfusion in Patient 2 suggests a
threshold effect for perfusion of the anterior and middle cerebral artery watershed territories. That is, perhaps a small increase in total Hb or
blood volume to some minimum critical value that occurred early in transfusion was sufficient to improve blood flow to certain blood vessels by
overcoming steal or other abnormalities of cerebral autoregulation.
Effects of vasculopathy and transfusion on cerebral tissue hemoglobin saturation (SCTO2). Cerebral tissue is relatively desaturated on
886Quinn and Dowling
Pediatr Blood Cancer DOI 10.1002/pbc
Currently, transfusion is guided mainly by an imperfect laboratory
goal of maintaining the percentage of Hb S at 30% or less.
Our study has several limitations. First, we did not measure the
partial pressure of oxygen (PO2) in cerebral or jugular vessels,
because this would require prohibitively invasive sampling, so we
cannot necessarily infer that desaturation is associated with
desaturation is likely a morbid condition given the neurophysiol-
ogy of SCD outlined above. Second, given the cross-sectional
study design, we cannot conclude that cerebral desaturation
precedes and causes neurologic injury. Although this is a reason-
able pathophysiologic conjecture, further prospective studies will
need to confirm this link. Third, the mean interval between mea-
surement of SCTO2and TCD studies was long (278 days), and this
may have obscured important relationships. Fourth, we could only
measure SCTO2in a limited region of mainly gray matter in the
watershed zone between the anterior and middle cerebral arteries
of the frontal lobes due to the requirements of probe placement on
glabrous skin. We were not able to interrogate other important
vascular territories or deep white matter. Fifth, excessive skull
thickness could interfere with some measurements of SCTO2by
erroneously providing measurements of bone marrow Hb satura-
tion (instead of or in addition to cerebral tissue Hb saturation). We
did not measure skull thickness in these patients, so we can not
exclude this possibility; however, our findings of right-left differ-
ences in SCTO2within patients and the minimization of right-left
differences with transfusion argues against this possibility in all
patients (because the medullary compartment of the frontal bone
is a contiguous space). Moreover, a measurement of SCTO2that
included (erroneously) bone marrow would give an apparently
higher value of SCTO2than the true SCTO2, because Hb saturation
is normally higher in bone marrow than cerebral tissue ,
indicating that we might have under-estimated the degree of
desaturation in some individuals. Finally, stored packed red
blood cells (PRBCs) lose 2,3-bisphosphoglycerate with time and
consequently develop increased Hb oxygen affinity. As such,
the increases in SCTO2that we observed following transfusion
could, at least in part, be explained by abnormally increased
oxygen affinity (which would actually impair oxygen delivery
to tissues). However, we transfused PRBCs stored for 7 days or
less to minimize this effect. Serial post-transfusion sampling
including measurements of the PO2in blood will be needed to
address this question fully. The main strengths of this study,
different from past reports, include the use of absolute cerebral
oximetry, large sample size, and a pre-specified sample size and
In conclusion, cerebral desaturation is a common neurophysi-
ologic abnormality in children with SCD. Cerebral desaturation is
associated with peripheral desaturation, more severe anemia, and
increasing age. Because SCTO2reflects the balance between cere-
bral tissue oxygen supply and demand, it is a physiologic bio-
marker for brain at risk of ischemic injury. This biomarker, which
is measured by a rapid non-invasive technique, should be studied
further to establish whether it can improve the identification of
children with SCD at highest risk of neurologic injury and
possibly serve as a physiologic monitoring parameter for
The authors would like to thank Roxana Mars, Pamela Hoof,
and Ellen Skalski who obtained all the measurements of cerebral
tissue saturation for this study and Leah Adix who collected and
maintained the data for this study. We thank Dr. George Buchanan
for his mentorship and thoughtful review of this manuscript. This
work was supported by grants from the National Institutes of
Health (grant no. KL2-RR024983 to C.T.Q. and M.M.D.) and
First American Real Estate Services, Inc. (to M.M.D.).
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Pediatr Blood Cancer DOI 10.1002/pbc