Haemoglobin oxygen saturation is a determinant of cerebral artery blood flow velocity in children with sickle cell anaemia

Article (PDF Available)inBritish Journal of Haematology 145(4):500-5 · April 2009with24 Reads
DOI: 10.1111/j.1365-2141.2009.07652.x · Source: PubMed
Abstract
Steady-state haemoglobin (Hb) desaturation is a common finding in sickle cell anaemia (Hb SS) that could predispose to stroke by limiting oxygen delivery to the brain. To determine its association with the risk of overt stroke, we examined the relationship between daytime Hb saturation measured by pulse oximetry (SpO(2)) and cerebral artery blood flow velocity measured by transcranial Doppler ultrasonography (TCD), an established risk factor for overt stroke in Hb SS. We studied 181 children using multivariate models to control for known determinants of TCD velocity, including age, haematocrit, and a measure of stenosis. We found that SpO(2) correlated significantly and inversely with TCD velocity in both the right and left middle cerebral arteries. Hb desaturation was associated with increased cerebral artery blood flow velocities and increased odds of abnormal TCD velocities, hence increased risk of stroke. About 5% of the variation in TCD velocity could be ascribed to Hb saturation while controlling for other determinants of TCD velocity. In conclusion, Hb saturation is a determinant of TCD velocity and a risk factor for stroke in children with Hb SS.
Haemoglobin oxygen saturation is a determinant of cerebral
artery blood flow velocity in children with sickle cell anaemia
Steady-state haemoglobin (Hb) desaturation is common in
patients with sickle cell anaemia (Hb SS) (Quinn & Ahmad,
2005). It has several causes, including a rightward shift of the
oxy-haemoglobin dissociation curve due to chronic anaemia
(Needleman et al, 1999) and the properties of sickle Hb in
solution (Seakins et al, 1973; Ueda et al, 1979). Hb desatura-
tion was once thought to be relatively benign, but it has now
been associated with several complications of Hb SS. Noctur-
nal Hb desaturation appears to increase the frequency of acute
painful episodes (Hargrave et al, 2003) and central nervous
system events, such as seizures, transient ischaemic attacks and
strokes (Kirkham et al, 2001). Recently, we showed that
daytime steady-state Hb desaturation is also a risk factor for
clinically overt stroke in children with Hb SS (Quinn &
Sargent, 2008).
The mechanisms by which Hb desaturation could con-
tribute to the risk of stroke are not entirely clear. Setty et al
(2003) showed that nocturnal oxygen desaturation in
patients with sickle cell disease was associated with endo-
thelial, leucocyte, and erythrocyte activation and adhesion as
well the release of pro-adhesive and pro-inflammatory
mediators. These pathophysiological events could lead to
vaso-occlusion and stroke. Hb desaturation also decreases
arterial oxygen content and, potentially, oxygen delivery to
the brain (Jones et al, 1981; Gupta et al, 1997). This could
also predispose to stroke in patients with Hb SS, especially
in regions of the brain distal to stenotic cerebral vasculo-
pathy.
We wished to better understand the relationship between
Hb desaturation and stroke in Hb SS. Increased cerebral artery
blood flow velocity, as measured by transcranial Doppler
ultrasonography (TCD), is an established risk factor for overt
stroke in children with Hb SS (Adams et al, 1992). Higher
TCD velocities are associated with higher risk of stroke.
Therefore, we investigated the association between daytime Hb
saturation and TCD velocity. We hypothesised that daytime
Hb saturation correlated inversely with TCD velocity, because
Hb desaturation should cause a compensatory increase in
cerebral blood flow velocity to maintain oxygen delivery to the
brain (Gupta et al, 1997).
Charles T. Quinn,
1,3
Jennifer Variste
3
and Michael M. Dowling
2,3
1
Hematology-Oncology and
2
Pediatric Neurology,
Department of Pediatrics, UT Southwestern
Medical Center, Dallas, TX, USA, and
3
Children’s
Medical Center Dallas, Dallas, TX, USA
Received 18 November 2008; accepted for
publication 9 February 2009
Correspondence: Charles T. Quinn, U.T.
Southwestern Medical Center, 5323 Harry Hines
Blvd., Dallas, TX 75390-9063, USA.
E-mail: charles.quinn@utsouthwestern.edu
Summary
Steady-state haemoglobin (Hb) desaturation is a common finding in sickle
cell anaemia (Hb SS) that could predispose to stroke by limiting oxygen
delivery to the brain. To determine its association with the risk of overt
stroke, we examined the relationship between daytime Hb saturation
measured by pulse oximetry (SpO
2
) and cerebral artery blood flow velocity
measured by transcranial Doppler ultrasonography (TCD), an established
risk factor for overt stroke in Hb SS. We studied 181 children using
multivariate models to control for known determinants of TCD velocity,
including age, haematocrit, and a measure of stenosis. We found that SpO
2
correlated significantly and inversely with TCD velocity in both the right and
left middle cerebral arteries. Hb desaturation was associated with increased
cerebral artery blood flow velocities and increased odds of abnormal TCD
velocities, hence increased risk of stroke. About 5% of the variation in TCD
velocity could be ascribed to Hb saturation while controlling for other
determinants of TCD velocity. In conclusion, Hb saturation is a determinant
of TCD velocity and a risk factor for stroke in children with Hb SS.
Keywords:sickle cell disease, stroke, risk factor, pulse oximetry, transcranial
Doppler ultrasonography.
research paper
First published online 6 March 2009
doi:10.1111/j.1365-2141.2009.07652.x ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505
Methods
Overview and study subjects
We performed a cross-sectional study of the Dallas newborn
cohort (DNC), a newborn inception cohort of children with
sickle cell disease (Quinn et al, 2004), to determine whether
daytime Hb saturation correlated with TCD measurements of
cerebral artery blood flow velocity. We studied all cohort
patients with Hb SS or sickle-b
0
-thalassaemia (Hb Sb
0
) who
had screening TCD studies for clinical care. We analysed
patients with Hb SS and Hb Sb
0
together because the
diseases are clinically indistinguishable and Hb Sb
0
is
uncommon.
Definitions and measurements
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). The highest TAMMV in each artery was used for
analysis, consistent with clinical care. We also used the single
highest TAMMV in the entire VB, consistent with clinical
care, so we could not study the individual contributions of the
three arteries in the VB. Only the first TCD study of any
patient was used, so each patient was represented only once in
each analysis. TCD examinations were performed according to
the stroke prevention in sickle cell anaemia (STOP) study
protocol (Adams et al, 1998) by a STOP-certified technician
using a non-imaging system (2-Mhz pulsed Doppler ultraso-
nograph, model TC8080; Nicolet Viasys Healthcare, Madison,
WI, USA).
We measured Hb saturation in room air (SpO
2
) during
‘well’ clinic visits by trained clinical technicians using the
Nellcor N-395 pulse oximeter (Nellcor Puritan Bennett Inc.,
Pleasanton, CA, USA). We recorded the daytime SpO
2
that was
nearest to the date of TCD study.
Known determinants of TCD velocity (TAMMV) include
age, haematocrit (Hct), metabolic demands, and degree of
stenosis (Taormina & Nichols, 1996). To control for these
confounders in our analysis of the effect of SpO
2
on TAMMV
we recorded the patient’s age at the time of the TCD study and
his or her most recent Hct (relative to the time of the TCD
study). All patients were supine, still, and quietly awake during
TCD measurements, consistent with clinical care, to ensure
similar metabolic demands.
We did not have a direct measurement of degree of
stenosis, because this is not provided by TCD. Further, there
is no ‘gold standard’ for the measurement of degree of
stenosis besides conventional radiocontrast angiography,
which our patients did not undergo because of its increased
risk in SCD patients and the lack of a medical indication for
the study. There is also no validated measure of degree of
stenosis by magnetic resonance angiography. Therefore, we
developed a novel, proxy measurement of stenosis by
considering the ratio of the TAMMV in the artery of interest
(e.g. RMCA or LMCA) to the TAMMV in the VB in the
same patient. Sickle cerebral vasculopathy is rare in the
vertebrobasilar system, so VB blood flow velocity will be
dependent on physiological factors, such as age, Hct,
metabolic demand, and SpO
2
, rather than stenosis. As such,
this ratio (e.g. RMCA:VB) should provide a reasonable
approximation of the proportion of the TAMMV in the
artery of interest (e.g. RMCA) that might be due to stenosis
and not age, Hct, metabolic demands, and SpO
2
. We tested
the characteristics of this proxy measure before including it
in statistical models.
Statistical analysis
Summary statistics were calculated for all variables of interest.
We used Spearman correlation to test the two primary
hypotheses that SpO
2
was inversely correlated with TAMMV
in the RMCA and LMCA. We pre-specified that these two
vessels would be used in the primary hypothesis tests. We
chose these two vessels because they are interrogated by TCD
for the determination of risk of stroke and we knew that dICA
measurements were not always obtained. Correlations with
other vessels and between other variables of interest were
performed as exploratory analyses. We compared the charac-
teristics of MCA:VB as a proxy measure of degree of stenosis to
the expected performance of such a measure. Group medians
were compared using the Kruskal–Wallis test.
If we found SpO
2
to be significantly correlated with
TAMMV, we then planned to perform multiple linear
regression to estimate the effect of SpO
2
on TAMMV in
the right and left MCA while simultaneously controlling for
age, Hct and stenosis. We tested for multicollinearity and the
required assumptions of multiple linear regression. We also
planned to model the odds of having an abnormal TCD
velocity (200 cm/s) given SpO
2
using multiple logistic
regression to simultaneously control for age, Hct and
stenosis. Receiver-operating characteristic (ROC) curves
would be generated, if appropriate, using the predicted
probabilities from the logistic regression model as the test
variable and abnormal TCD velocity as the dichotomous state
variable. These logistic regression models would not be useful
clinically as predictive tools, because a measure of stenosis is
a covariate; rather, these models would define the relative
physiological contributions of age, Hct, SpO
2
and stenosis to
TAMMV.
Data were analysed using spss version 17 statistical software
for Mac (SPSS, Inc., Chicago, IL, USA). Subjects with missing
measurements were excluded from each analysis; no data were
imputed. Because we had two primary hypothesis tests, we
nominally controlled for multiple statistical comparisons
study-wide by considering only Pvalues less than 0Æ025 to be
statistically significant.
Hb Saturation is a Determinant of TCD Velocity
ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505 501
Results
Characteristics of patients
We identified 181 patients who had screening TCD studies;
53Æ8% were male and 97Æ8% had Hb SS. Of these, 167 (92%)
and 181 (100%) had measurements of SpO
2
and Hct available
for analysis. Characteristics of the patients are shown in
Table I. The median interval between the TCD study and the
most recent Hct and SpO
2
was 28 and 49 d, respectively.
Fourteen patients had received a transfusion in the 3 months
preceding the TCD study. None of the patients was transfused
or prescribed hydroxycarbamide in the interval between the
TCD study and the measurements of Hct and SpO
2
. Some
arteries could not be insonated in a minority of patients due to
technical difficulties, patient non-compliance, or severe steno-
sis (Table I).
Correlation of SpO
2
with TAMMV
Daytime SpO
2
was found to correlate significantly with
TAMMV in the right and left MCA in the direction
hypothesised (Fig 1; Table II). Lower Hb saturations were
associated with higher TAMMVs. The same relationship was
demonstrated in the anterior and posterior circulations
(Table II). Age and Hct were also inversely correlated with
SpO
2
(data not shown), a previously described relationship
(Quinn & Ahmad, 2005).
Characteristics of the proxy measure of stenosis
We evaluated the characteristics of the MCA:VB ratio as proxy
measure for degree of stenosis. As would be theoretically
expected, MCA:VB was not significantly correlated with SpO
2
,
Hct, or age, but it did correlate with the TAMMV in the MCA
on the same side (Table III). Further, MCA:VB was higher in
patients who had elevated TAMMVs (170 cm/s) in the MCA
on the same side compared to patients whose TAMMVs were
not elevated. The median MCA:VB was 1Æ3, 1Æ5, and 1Æ6 for
patients with normal (<170 cm/s), conditional (170–199
cm/s), and abnormal (200 cm/s) TAMMVs, respectively
(P=0Æ001). Because we planned to use MCA:VB as a
predictor (covariate) of TAMMV in the MCA in multivariate
models, the expected correlation between MCA and MCA:VB
Table I. Patient characteristics.
Variable Mean Median
10th–90th
percentiles n*
Age (years) 8Æ07Æ43Æ2–13Æ5 181
Hct (%) 22Æ822Æ217Æ8–28Æ1 181
SpO
2
(%) 96Æ697Æ0 92–100 167
TCD velocities (cm/s)
RMCA 143 141 104–183 178
LMCA 150 148 103–189 175
RACA 121 122 80–162 164
LACA 118 115 82–154 157
RdICA 122 122 79–126 82
LdICA 124 121 85–166 82
VB 108 106 79–135 168
Proxy for stenosis
RMCA:VB 1Æ37 1Æ33 1Æ03–1Æ74 166
LMCA:VB 1Æ43 1Æ37 1Æ02–1Æ92 165
Hct, haematocrit; SpO
2
, pulse oximetry; TCD, transcranial Doppler
ultrasonography; RMCA, right middle cerebral artery; LMCA, left
middle cerebral artery; RACA, right anterior cerebral artery; LACA, left
anterior cerebral artery; RdICA, right distal internal carotid artery;
LdICA, left distal internal carotid artery; VB, vertebrobasilar system.
*Number of subjects who had data for analysis of each variable.
(A) (B)
Fig 1. Correlation between Hb saturation and cerebral artery blood flow velocity (TAMMV). Panels (A) and (B) show the correlations in the right
and left middle cerebral arteries, respectively. Also shown are the regression line and its 95% confidence interval (dotted lines).
C. T. Quinn, J. Variste and M. M. Dowling
502 ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505
might have limited its usefulness. However, RMCA explained
only 16% of the variation in RMCA:VB, and LMCA explained
only 22% of the variation in LMCA:VB, indicating that the
majority of the variation in MCA:VB is unrelated to simply the
TAMMV in the MCA. All these characteristics supported
the use of MCA:VB as a proxy measure for degree of stenosis in
the multivariate models.
Multivariate models
We then performed multiple linear regression with stepwise
selection using the TAMMV in the right or left MCA as the
dependent variable and age, Hct, SpO
2
and the proxy measure
of stenosis (MCA:VB) as the independent variables. The
distribution of SpO
2
was right-skewed, but transformation of
SpO
2
to a normal distribution did not change the performance
of the models. Therefore, we did not transform SpO
2
in the
final models. The residual analyses suggested that the distri-
butions were reasonably close to normal, linear, and homo-
scedastic. We found a significant linear relationship between
SpO
2
and the TAMMV in both the right and left MCA while
controlling for age, Hct and the proxy measure of stenosis
(Table IV). As expected, lower SpO
2
was associated with
higher TAMMVs. Age and Hct were also inversely correlated
with TAMMV. The proxy measure of stenosis (MCA:VB) was
directly associated with TAMMV. Overall, the models
explained about half the variation in TAMMV, and SpO
2
explained about 5% of the variation while controlling for
covariates.
We then modeled the odds of having an abnormal TCD
velocity (TAMMV 200 cm/s) in either the right or the left
MCA. While simultaneously controlling for age, Hct and the
proxy measure of stenosis (MCA:VB), we found that each unit
(1% absolute) decrease in SpO
2
gave an odds ratio for an
abnormal TCD velocity of 1Æ3 in the RMCA (P=0Æ021) and
1Æ4 in the LMCA (P=0Æ010). Figure 2 shows the ROC curves
for prediction of abnormal TCD velocity by the models. The
areas under the ROC curves were 0Æ90 (P<0Æ001) and 0Æ93
(P<0Æ001) for the RMCA and LMCA, indicating excellent
prediction of abnormal TCD velocities.
Discussion
This study showed that daytime Hb saturation is a determinant
of TCD velocity in children with Hb SS. Desaturation was
associated with increased cerebral artery blood flow velocities
and increased odds of abnormal TCD velocities, thus increased
risk of stroke. A similar inverse relationship between Hb
saturation and TCD velocity was shown in a small (n= 30),
uncontrolled study of determinants of intellectual function in
children with Hb SS (Hogan et al, 2006). Here, we controlled
for confounders of TCD velocity in a much larger sample and
showed that about 5% of the variation in TCD velocity could
be ascribed to Hb saturation alone. Although stenosis itself is
the dominant risk factor, our study adds to a growing body of
evidence for an additional role of Hb desaturation in the
pathophysiology of stroke in Hb SS (Kirkham et al, 2001; Setty
et al, 2003; Hogan et al, 2006; Kirkham & Datta, 2006; Quinn
& Sargent, 2008). We propose that desaturation, which
decreases arterial oxygen content, limits oxygen delivery to
the brain and predisposes to stroke, especially in regions distal
to stenotic cerebral vasculopathy where compensatory
increases in blood flow may be blunted. Moreover, the
Table II. Correlations between SpO
2
and TCD velocities.
Artery Spearman qP
RMCA )0Æ216 0Æ006
LMCA )0Æ244 0Æ002
RACA )0Æ269 0Æ001
LACA )0Æ192 0Æ020
RdICA )0Æ240 0Æ028
LdICA )0Æ278 0Æ012
VB )0Æ238 0Æ003
SpO
2
, pulse oximetry; TCD, transcranial Doppler ultrasonography;
RMCA, right middle cerebral artery; LMCA, left middle cerebral artery;
RACA, right anterior cerebral artery; LACA, left anterior cerebral
artery; RdICA, right distal internal carotid artery; LdICA, left distal
internal carotid artery; VB, vertebrobasilar system.
Table III. Correlations between the proxy measure of stenosis and age,
Hct, SpO
2
, and TAMMV in the right and left MCA.
RMCA:VB LMCA:VB
Spearman qPSpearman qP
Age )0Æ157 0Æ044 )0Æ035 0Æ652
Hct 0Æ104 0Æ183 0Æ052 0Æ510
SpO
2
0Æ54 0Æ511 )0Æ25 0Æ763
TAMMV 0Æ437* <0Æ001 0Æ517<0Æ001
Hct, haematocrit; SpO
2
, pulse oximetry; TAMMV, time-averaged
maximum mean velocity.
*Correlation with TAMMV in the RMCA.
Correlation with TAMMV in the LMCA.
Table IV. Predictors of TAMMV in the right and left MCA.
TAMMV in RMCA TAMMV in LMCA
bpartial r
2
Pbpartial r
2
P
Intercept 367Æ26 – 310Æ52 ––
Age )3Æ03 0Æ18 <0Æ001 )2Æ12 0Æ10 <0Æ001
Hct )3Æ20 0Æ19 <0Æ001 )3Æ25 0Æ20 <0Æ001
SpO
2
)1Æ98 0Æ06 0Æ002 )1Æ57 0Æ04 0Æ017
MCA:VB 46Æ79 0Æ28 <0Æ001 56Æ67 0Æ42 <0Æ001
model r
2
=0Æ50 model r
2
=0Æ52
Hct, haematocrit; SpO
2
, pulse oximetry; TAMMV, time-averaged
maximum mean velocity; MCA, middle cerebral artery; VB, verte-
brobasilar system.
Hb Saturation is a Determinant of TCD Velocity
ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505 503
compensatory increase in cerebral blood flow due to desatu-
ration could increase the turbulence of blood flow at the site of
stenosis and further predispose to vessel injury and stroke.
Our findings do not yet directly affect clinical practice, but
they add to our knowledge about the genesis of stroke in Hb SS
and have at least two additional implications. First, the
measurement of cerebral artery blood flow velocity by TCD is
more complex than a simple measure of the degree of stenosis
in a blood vessel. Although stenosis is a dominant factor, TCD
is actually a composite measure that integrates a number of
related factors that could increase the risk of stroke in children
with Hb SS, including the degree of anaemia and Hb
saturation. Second, Hb saturation is a potentially modifiable
risk factor. Supplemental oxygen would be cumbersome to use,
but treatment with hydroxycarbamide (Singh et al, 2008) or
red blood cell transfusions (Kress et al, 1999) can alleviate
desaturation in Hb SS, which might be part of the therapeutic
benefit of both agents.
Our study has a number of limitations. First, we cannot
ascribe a causal relationship between Hb desaturation and
TCD velocity because this is a cross-sectional study. Even so,
our findings are consistent with controlled physiological
experiments in animal models (Jones et al, 1981) and humans
without Hb SS (Gupta et al, 1997). Second, we used a novel
proxy measure of degree of stenosis (MCA:VB). We used this
proxy because there is no appropriate ‘gold standard’ for
children with Hb SS. Nevertheless, this proxy is supported by
biological rationale, and it performed as expected for a
measure of degree of stenosis. Additionally, the significant
inverse relationship between SpO
2
and TCD velocity remains if
we remove this proxy measure from the models entirely (data
not shown). That is, our conclusions are the same with or
without the use of MCA:VB as a covariate, but the inclusion of
MCA:VB may improve the accuracy of our models. Third, we
retrospectively assembled data that were obtained and docu-
mented for the purposes of routine clinical practice, so there
were missing data and the possibility of different types of bias,
such as ascertainment bias. However, we analysed every patient
in our cohort who had a screening TCD study, and 92% and
100% of patients had measurements of SpO
2
and Hct,
respectively. Fourth, the measurements of SpO
2
and Hct were
not simultaneous with the TCD study, because this is not our
clinical practice, but the median interval between the TCD and
these measurements was short (1–1Æ5 months). Finally, we did
not ascertain patients’ oxy-haemoglobin dissociation curves, so
we do not know whether desaturated patients are hypoxaemic
and cannot quantify oxygen extraction. Nevertheless, Hb
concentration and saturation are the dominant determinants
of arterial oxygen content, so anaemia and Hb desaturation
will greatly limit the bulk delivery of oxygen to the brain
irrespective of dissolved oxygen content.
In conclusion, Hb saturation is a determinant of TCD
velocity in children with Hb SS. Desaturation is associated with
increased cerebral artery blood flow velocities and increased
odds of abnormal TCD velocities, thus increased risk of stroke.
Hb saturation is an easily measured and potentially modifiable
risk factor. It could be studied as a potential therapeutic target
to prevent stroke.
(A) (B)
AUC = 0.90
(P < 0.001)
AUC = 0.93
(P < 0.001)
Fig 2. Receiver-operating characteristic (ROC) curves for the prediction of abnormal TCD velocities by Hb saturation. Panels (A) and (B) show the
ROC curves for the prediction of abnormal TCD velocities (200 cm/s) in the right and left middle cerebral arteries, respectively, using a combination
of Hb saturation, haematocrit, age, and a proxy measure of degree of stenosis as predictors. The x-axis indicates the false positive rate (1 – specificity).
The y-axis indicates sensitivity (the proportion of patients who were correctly classified).
C. T. Quinn, J. Variste and M. M. Dowling
504 ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505
Acknowledgements
We thank Drs George Buchanan and Naveed Ahmad for their
review of this manuscript. This work was supported in part by
grants from the National Institutes of Health (CTQ and MMD:
U54-HL70588, KL2-RR024983) and First American Real Estate
Services, Inc. (MMD).
Authors’ contributions
C.T.Q. and M.M.D. designed the study, supervised the
collection of the data, analysed the data, and wrote the
manuscript. J.V. collected the data and wrote the manuscript.
References
Adams, R., McKie, V., Nichols, F., Carl, E., Zhang, D.L., McKie, K.,
Figueroa, R., Litaker, M., Thompson, W. & Hess, D. (1992) The use
of transcranial ultrasonography to predict stroke in sickle cell dis-
ease. The New England Journal of Medicine,326, 605–610.
Adams, R.J., McKie, V.C., Hsu, L., Files, B., Vichinsky, E., Pegelow, C.,
Abboud, M., Gallagher, D., Kutlar, A., Nichols, F.T., Bonds, D.R. &
Brambilla, D. (1998) Prevention of a first stroke by transfusions in
children with sickle cell anemia and abnormal results on transcranial
Doppler ultrasonography. The New England Journal of Medicine,
339, 5–11.
Gupta, A.K., Menon, D.K., Czosnyka, M., Smielewski, P. & Jones, J.G.
(1997) Thresholds for hypoxic cerebral vasodilation in volunteers.
Anesthesia & Analgesia,85, 817–820.
Hargrave, D.R., Wade, A., Evans, J.P., Hewes, D.K. & Kirkham, F.J.
(2003) Nocturnal oxygen saturation and painful sickle cell crises in
children. Blood,101, 846–848.
Hogan, A.M., Pit-ten Cate, I.M., Vargha-Khadem, F., Prengler, M. &
Kirkham, F.J. (2006) Physiological correlates of intellectual function
in children with sickle cell disease: hypoxaemia, hyperaemia and
brain infarction. Developmental Science,9, 379–387.
Jones, Jr, M.D., Traystman, R.J., Simmons, M.A. & Molteni, R.A.
(1981) Effects of changes in arterial O
2
content on cerebral blood
flow in the lamb. American Journal of Physiology,240, H209–H215.
Kirkham, F.J. & Datta, A.K. (2006) Hypoxic adaptation during
development: relation to pattern of neurological presentation and
cognitive disability. Developmental Science,9, 411–427.
Kirkham, F.J., Hewes, D.K., Prengler, M., Wade, A., Lane, R. &
Evans, J.P. (2001) Nocturnal hypoxaemia and central-
nervous-system events in sickle-cell disease. The Lancet,357,
1656–1659.
Kress, J.P., Pohlman, A.S. & Hall, J.B. (1999) Determination of
hemoglobin saturation in patients with acute sickle chest syndrome:
a comparison of arterial blood gases and pulse oximetry. Chest,115,
1316–1320.
Needleman, J.P., Setty, B.N., Varlotta, L., Dampier, C. & Allen, J.L.
(1999) Measurement of hemoglobin saturation by oxygen in chil-
dren and adolescents with sickle cell disease. Pediatric Pulmonology,
28, 423–428.
Quinn, C.T. & Ahmad, N. (2005) Clinical correlates of steady-state
oxyhaemoglobin desaturation in children who have sickle cell dis-
ease. British Journal of Haematology,131, 129–134.
Quinn, C.T. & Sargent, J.W. (2008) Daytime steady-state haemo-
globin desaturation is a risk factor for overt stroke in children
with sickle cell anaemia. British Journal of Haematology,140, 336–
339.
Quinn, C.T., Rogers, Z.R. & Buchanan, G.R. (2004) Survival of chil-
dren with sickle cell disease. Blood,103, 4023–4027.
Seakins, M., Gibbs, W.N., Milner, P.F. & Bertles, J.F. (1973) Erythro-
cyte Hb-S concentration. An important factor in the low oxygen
affinity of blood in sickle cell anemia. Journal of Clinical Investiga-
tion,52, 422–432.
Setty, B.N., Stuart, M.J., Dampier, C., Brodecki, D. & Allen, J.L. (2003)
Hypoxaemia in sickle cell disease: biomarker modulation and rele-
vance to pathophysiology. The Lancet,362, 1450–1455.
Singh, S.A., Koumbourlis, A.C. & Aygun, B. (2008) Resolution of
chronic hypoxemia in pediatric sickle cell patients after treat-
ment with hydroxyurea. Pediatric Blood and Cancer,50, 1258–
1260.
Taormina, M.A. & Nichols, F.T. 3rd (1996) Use of transcranial
Doppler sonography to evaluate patients with cerebrovascular dis-
ease. Neurosurgery Clinics of North America,7, 589–603.
Ueda, Y., Nagel, R.L. & Bookchin, R.M. (1979) An increased Bohr
effect in sickle cell anemia. Blood,53, 472–480.
Hb Saturation is a Determinant of TCD Velocity
ª2009 Blackwell Publishing Ltd, British Journal of Haematology,145, 500–505 505
    • "In addition, nocturnal hypoxaemia is associated with a greater risk of future central nervous system events (stroke, transient ischaemic attacks and seizures) (Kirkham et al, 2001). It is known that hypoxaemia can affect the adhesion characteristics of red blood cells to the cerebral endothelium (Setty & Stuart, 1996; Setty et al, 2003 ), and that haemoglobin desaturation is associated with increased cerebral artery blood flow velocities (Quinn et al, 2009). Increased TCD velocities with even abnormal neuropsychological function have been reported in snoring non-SCD patients despite normoxaemia (Hill et al, 2006 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Children with sickle cell disease (SCD) have a significant vascular morbidity, especially cerebral macrovasculopathy (CV), detectable by transcranial Doppler. This study aimed to identify risk factors for CV using longitudinal biological and clinical data in a SCD newborn cohort followed at the Robert Debre Reference centre (n = 375 SS/Sβ(0) ). Median follow-up was 6·8 years (2677 patient-years). Among the 59 children presenting with CV, seven had a stroke. Overall, the incidence of CV was 2·20/100 patient-years [95% confidence interval (95% CI): 1·64-2·76] and the incidence of stroke was 0·26/100 patient-years (95% CI: 0·07-0·46). The cumulative risk of CV by age 14 years was 26·0% (95% CI: 20·0-33·3%). Risk factors for CV were assessed by a Cox model encompassing linear multivariate modelling of longitudinal quantitative variables. Years per upper-airway obstruction [Hazard ratio (HR) = 1·47; 95% CI: 1·05-2·06] or bronchial obstruction (HR = 1·76; 95% CI: 1·49-2·08) and reticulocyte count (HR = 1·82 per 50 × 10(9) /l increase; 95% CI: 1·10-3·01) were independent risk factors whereas fetal haemoglobin level (HR = 0·68 per 5% increase; 95% CI: 0·48-0·96) was protective. Alpha-thalassaemia was not protective in multivariate analysis (ancillary analysis n = 209). Specific treatment for upper or lower-airway obstruction and indirect targeting of fetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV.
    Full-text · Article · Jan 2016
    • "Lower daytime and nocturnal SpO 2 in SCA are associated with poor clinical outcomes. This includes elevated cerebral blood flow velocities [1, 2] and an increased risk of stroke [3, 23]. Co-inheritance of alpha-thalassemia is protective against elevated cerebral blood flow velocities in children with SCA [24, 25] and is associated with reduced stroke risk [26], whilst G6PD increases the risk [24]. "
    [Show abstract] [Hide abstract] ABSTRACT: Low hemoglobin oxygen saturation (SpO2) is common in Sickle Cell Anemia (SCA) and associated with complications including stroke, although determinants remain unknown. We investigated potential hematological, genetic, and nutritional predictors of daytime SpO2 in Tanzanian children with SCA and compared them with non-SCA controls. Steady-state resting pulse oximetry, full blood count, transferrin saturation, and clinical chemistry were measured. Median daytime SpO2 was 97% (IQ range 94-99%) in SCA (N = 458), lower (P < 0.0001) than non-SCA (median 99%, IQ range 98-100%; N = 394). Within SCA, associations with SpO2 were observed for hematological variables, transferrin saturation, body-mass-index z-score, hemoglobin F (HbF%), genotypes, and hemolytic markers; mean cell hemoglobin (MCH) explained most variability (P < 0.001, Adj r (2) = 0.09). In non-SCA only age correlated with SpO2. α-thalassemia 3.7 deletion highly correlated with decreased MCH (Pearson correlation coefficient -0.60, P < 0.0001). In multivariable models, lower SpO2 correlated with higher MCH (β-coefficient -0.32, P < 0.001) or with decreased copies of α-thalassemia 3.7 deletion (β-coefficient 1.1, P < 0.001), and independently in both models with lower HbF% (β-coefficient 0.15, P < 0.001) and Glucose-6-Phosphate Dehydrogenase genotype (β-coefficient -1.12, P = 0.012). This study provides evidence to support the hypothesis that effects on red cell rheology are important in determining SpO2 in children with SCA. Potential mechanisms and implications are discussed.
    Full-text · Article · Apr 2013
    • "In SS disease, normal adult haemoglobin is replaced with sickle haemoglobin, which polymerizes when deoxygenated, distorting the red cells into a sickle shape that can occlude the microvasculature. The aetiology of the wide range of acute and chronic complications of SS disease remains unexplained, but there is an association with the degree of haemoglobin oxygen desaturation (Quinn et al. 2009), and alterations in the peripheral vasculature may be involved (Mohan et al. 1998, 2011; Sangkatumvong et al. 2011). Exposure to cold, fever and dehydration increase the risk of painful vaso-occlusive episodes, a common complication in SS disease, possibly because of increased sympathetic drive in response to these environmental triggers causing vasoconstriction. "
    [Show abstract] [Hide abstract] ABSTRACT: New Findings • What is the central question of this study? Autonomic nervous dysfunction is implicated in complications of sickle cell anaemia (SCA). In healthy adults, a deep inspiratory breath hold (IBH) elicits rapid transient SNS- mediated vasoconstriction detectable using Laser Doppler Flux (LDF) assessment of the finger-tip cutaneous micovasculature. • What is the main finding and its importance? We demonstrate significantly increased resting peripheral blood flow and sympathetic activity in African children with SCA compared to sibling controls and increased sympathetic stimulation in response to vasoprovocation with DIG. This study is the first to observe an inverse association between resting peripheral blood flow and haemoglobin oxygen saturation (SpO2). These phenomena may be an adaptive response to the hypoxic exposure in SCA. There is increasing evidence that autonomic dysfunction in adults with homozygous sickle cell (haemoglobin SS) disease is associated with enhanced autonomic nervous system-mediated control of microvascular perfusion. However, it is unclear whether such differences are detectable in children with SS disease. We studied 65 children with SS disease [38 boys; median age 7.2 (interquartile range 5.1–10.6) years] and 20 control children without symptoms of SS disease [8 boys; 8.7 (5.5–10.8) years] and recorded mean arterial blood pressure (ABP) and daytime haemoglobin oxygen saturation (). Cutaneous blood flux at rest (RBF) and during the sympathetically activated vasoconstrictor response to inspiratory breath hold (IBH) were measured in the finger pulp of the non-dominant hand using laser Doppler fluximetry. Local factors mediating flow motion were assessed by power spectral density analysis of the oscillatory components of the laser Doppler signal. The RBF measured across the two study groups was negatively associated with age (r=−0.25, P < 0.0001), ABP (r=−0.27, P= 0.02) and daytime (r=−0.30, P= 0.005). Children with SS disease had a higher RBF (P= 0.005) and enhanced vasoconstrictor response to IBH (P= 0.002) compared with control children. In children with SS disease, higher RBF was associated with an increase in the sympathetic interval (r=−0.28, P= 0.022). The SS disease status, daytime and age explained 22% of the variance in vasoconstrictor response to IBH (P < 0.0001). Our findings suggest that blood flow and blood flow responses in the skin of young African children with SS disease differ from those of healthy control children, with increased resting peripheral blood flow and increased sympathetic stimulation from a young age in SS disease. They further suggest that the laser Doppler flowmetry technique with inspiratory breath hold manoeuvre appears to be robust for use in young children with SS disease, to explore interactions between , ABP and autonomic function with clinical complications, e.g. skin ulceration.
    Full-text · Article · Jan 2013
Show more