Blood First Edition Paper, prepublished online April 11, 2007; DOI 10.

1182/blood-2006-11-057893

HYDROXYUREA THERAPY LOWERS

TRANSCRANIAL DOPPLER FLOW VELOCITIES
IN CHILDREN WITH SICKLE CELL ANEMIA
Short Title: Hydroxyurea lowers TCD velocities

Sherri A. Zimmerman, MD1, William H. Schultz, MHS, PA-C2,

Shelly Burgett, RN, PNP1, Nicole A. Mortier, MHS, PA-C2,
and Russell E. Ware, MD, PhD2

Duke Pediatric Sickle Cell Program and Division of Pediatric Hematology/Oncology,

Duke University Medical Center, Durham, NC; 2Department of Hematology, St. Jude
Childrens Research Hospital, Memphis TN

Correspondence:

Russell E. Ware MD PhD

Department of Hematology
St. Jude Childrens Research Hospital
332 N. Lauderdale St.
Memphis TN 38105
901-495-4238 (telephone)
901-495-4723 (fax)
e-mail: russell.ware@stjude.org

Key Words: Sickle Cell Anemia, Transcranial Doppler, Hydroxyurea

Copyright 2007 American Society of Hematology

ABSTRACT

Hydroxyurea has hematological and clinical efficacy in SCA, but its effects on
transcranial doppler (TCD) flow velocities remain undefined. Fifty-nine children initiating
hydroxyurea therapy for clinical severity had pre-treatment baseline TCD measurements;
37 with increased flow velocities (140 cm/sec) were then enrolled in an IRB-approved
prospective Phase II trial with TCD velocities measured at maximum tolerated dose
(MTD) and one year later. At hydroxyurea MTD (mean 1SD = 27.9 2.7 mg/kg/day),
significant decreases were observed in the right MCA (166 27 cm/sec to 135 27
cm/sec, p<.001) and left MCA velocities (168 26 cm/sec to 142 27 cm/sec, p<.001).
The magnitude of TCD velocity decline was significantly correlated with the maximal
baseline TCD value. At hydroxyurea MTD, 14 of 15 children with conditional baseline
TCD values improved, while 5 of 6 with abnormal TCD velocities whose families refused
transfusions became <200 cm/sec. TCD changes were sustained at follow-up. These
prospective data indicate that hydroxyurea can significantly decrease elevated TCD flow
velocities, often into the normal range. A multicenter trial is warranted to determine the
efficacy of hydroxyurea for the management of increased TCD values, and ultimately for
primary stroke prevention in children with SCA.

INTRODUCTION

Transcranial doppler (TCD) ultrasonography is now recommended as a routine

screening test for children with sickle cell anemia (SCA) from 2 to 16 years of age, to
identify patients at highest risk for primary stroke [1,2]. TCD studies measure flow
velocity within the large intracranial arteries, which are the vessels most often involved in
sickle cerebral vasculopathy and stroke [3,4]. TCD ultrasonography is particularly useful
in children because it is painless, non-invasive, relatively inexpensive, easy to perform,
and requires no sedation.
Landmark studies performed almost two decades ago by Adams and colleagues
[5] found that children with SCA have higher baseline TCD flow velocities than agematched children without SCA. These increased TCD velocities were related in part to
the anemia, since the TCD values were inversely correlated with the hematocrit [6].
Among children with SCA, however, increased TCD flow velocities have also been
associated with younger age and pathological arterial stenosis [7]. In the cohort of
patients from the Medical College of Georgia, 36.8% had TCD velocities 140 cm/sec,
17.5% had velocities 170 cm/sec termed conditional, and 7.9% had velocities 200
cm/sec termed abnormal [5,8,9].
Abnormal TCD velocities are identified in 5-10% of children with SCA and confer a
10% annual risk for developing primary stroke [8,9]. The NHLBI-sponsored multicenter
randomized Stroke Prevention (STOP) trial demonstrated that monthly blood transfusions
can reduce this stroke risk by 90% compared to observation alone [10], and a Clinical
Alert recommended chronic transfusions for children with SCA and abnormal TCD
velocities [11]. However, the follow-up STOP 2 study concluded that transfusions must
3

be continued indefinitely in this setting, due to an increased risk of conversion to

abnormal TCD velocities and the development of new neurological events after halting
transfusions [12]. Children with conditional TCD velocities also have an elevated (1-3%
annual) risk of developing primary stroke, most commonly after conversion to the
abnormal category [13]. Accordingly, frequent monitoring of children with conditional TCD
velocities is recommended, although no specific therapy is currently recommended for
this potentially vulnerable patient population.
An alternative effective therapy would be beneficial for children with SCA and
abnormal TCD velocities to reduce the long-term risks associated with chronic blood
transfusions, including erythrocyte alloimmunization, infectious risks, and iron overload
[14]. In addition, a simple treatment option might be beneficial for children with
conditional TCD values, who currently receive increased monitoring but no specific
treatment. The increasing availability of hydroxyurea therapy offers a reasonable
therapeutic option in these settings, but to date no prospective studies have focused on
the effects of hydroxyurea therapy on TCD velocities in children with SCA. The Belgian
registry recently reported a beneficial effect of hydroxyurea in 11 children who had
abnormal TCD and serial measurements, with a significant decrease observed in TCD
velocities [15]. A recent small retrospective analysis suggested that hydroxyurea
significantly decreased the TCD velocities compared to age-matched controls, but only 8
children had TCD velocities 140 cm/sec and the effects were not related to
hematological changes [16]. In the current study, we describe a prospective singleinstitution IRB-approved Phase II trial of hydroxyurea for children with SCA and increased
TCD flow velocities.

METHODS
TCD Screening. Beginning in 1995, the Duke Pediatric Sickle Cell Program enrolled
subjects in the Phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), and thereafter
began using hydroxyurea for the routine clinical management of selected children with
severe vaso-occlusive complications such as recurrent painful events and acute chest
syndrome. Routine TCD screening began at Duke in 1999, and analysis of the initial TCD
screening results provided the pilot data and rationale for a prospective Phase II trial to
determine the effects of hydroxyurea on TCD flow velocities.

Prospective Phase II Study. Between late 2000 and 2004, all pediatric patients with
severe forms of sickle cell anemia (HbSS, HbS/ 0-thalassemia, HbS/OArab) underwent
TCD screening before initiating hydroxyurea treatment. In most cases, these children
were prescribed hydroxyurea therapy for severe clinical complications (e.g., recurrent
pain or acute chest syndrome), including children who received hydroxyurea as part of an
open-label trial to determine the effects of hydroxyurea on organ function and quality of
life for young children (age 1-3 years) with SCA. Children initiating hydroxyurea therapy
who had increased baseline TCD flow velocities identified were eligible for a prospective
study to determine the effects of hydroxyurea on their TCD values.
All TCD screening studies were performed in the Neurodiagnostic Laboratory at
Duke University Medical Center using a non-duplex TCD instrument, according to the
published techniques for children with SCA [5]. Briefly, the left and right middle cerebral,
distal internal carotid, anterior cerebral, and posterior cerebral arteries were insonated at
2mm increments using a special pediatric transducer and a transtemporal approach.
Maximal systolic and diastolic peak velocities were recorded, but the time-averaged
5

maximum velocity (TAMV) was used to determine the TCD value for the major intracranial
arteries on each side, as previously described [5].
After TCD screening, those children with at least one increased TCD value
(defined as a right- or left-sided TAMV 140 cm/sec) were offered enrollment in an IRBapproved trial to determine prospectively the effects of hydroxyurea therapy on TCD
velocities. Approval for this prospective study was obtained from the Duke University
Medical Center Institutional Review Board and all subjects and families gave written
informed consent. Hydroxyurea dosing and monitoring were performed according to
routine clinical practice, including escalation to the maximum tolerated dose (MTD) with
monthly blood counts as previously described [17]. After a stable hydroxyurea MTD was
reached, typically after 6-12 months of therapy, a follow-up TCD study was performed. A
third long-term follow-up TCD study was then performed at least one year after reaching
MTD, to determine if there were sustained treatment effects. Baseline brain MRI/MRA
imaging was performed in children as part of this protocol, using standard techniques.

Statistical analysis. TCD flow velocities were recorded for the right and left middle
cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA).
Patient and treatment characteristics such as age, hydroxyurea dose, and routine blood
counts including % HbF values, were also recorded. Standard statistical calculations
such as mean standard deviation, median, and range were performed using Excel
software. Comparisons of TCD studies for a given patient, e.g. pre- and post-treatment
with hydroxyurea, were performed using the nonparametric Wilcoxon rank sum test while
between-group comparisons used a two-tailed t test. Regression plots to determine

correlations between parameters such as baseline TCD velocity and change in TCD
values were performed using SAS software (Cary, NC).
RESULTS

Initial TCD Screening. Analysis of the first 102 children who received TCD screening [18]
revealed fewer than expected children with conditional and abnormal flow velocities
(12.7% and 3.9% respectively), compared to Adamss published prevalence values of
17.5% and 7.9% [8,9]. Subsequent analysis of these initial screening results according to
concurrent hydroxyurea therapy revealed a significant difference: 28 children on
hydroxyurea therapy had an average TCD flow velocity of 116 25 cm/sec, while 74
children not on hydroxyurea therapy had an average TCD flow velocity of 141 32
cm/sec (p<.001, data not shown). These pilot data suggested that hydroxyurea therapy
might lead to decreased TCD flow velocities, but no baseline pre-treatment
measurements were available, and there were substantial differences between these two
patient cohorts (e.g., the hydroxyurea-treated children were older and had more clinical
severity). To test this hypothesis, we designed a prospective Phase II study to determine
the effects of hydroxyurea therapy on TCD flow velocities in children with SCA.

TCD screening for Phase II study eligibility. Over a 45-month period, 59 children with
SCA underwent TCD screening before initiating hydroxyurea therapy for clinical
indications (e.g., pain, ACS). A total of 37 children (62.7%) were identified with at least
one increased TCD velocity value 140 cm/sec (right MCA in 31, left MCA in 32, right
ACA in 12, and left ACA in 14 patients), all of whom were enrolled in the prospective
study. Only one child had an elevated PCA flow velocity of 156 cm/sec on the left side.
7

Fifteen children (25.4%) had at least one conditional TCD value between 170 and 199
cm/sec (right MCA in 11, left MCA in 10, right ACA in 3, and left ACA in 1 patient). Six
other children (10.2%) had at least one abnormal TCD value 200 cm/sec (right MCA in
3 and left MCA in 5 patients); their families declined transfusions and elected to proceed
with hydroxyurea therapy as already planned for clinical severity.

Baseline MRI/MRA results. A total of 33 children completed baseline brain MRI and MRA
studies, typically within 2 months of initiating hydroxyurea therapy; 4 children were unable
to complete the study. Eleven children had abnormal MRI results, 10 had abnormal MRA
findings, and 2 had both abnormal MRI and MRA results. Thirteen children with abnormal
MRI findings included 11 with small T2-weighted bright foci consistent with small vessel
ischemia, and 3 with an unsuspected Arnold Chiari Type I malformation. Twelve children
with abnormal MRA findings included 9 with mild vessel narrowing, 2 with moderate
vessel stenosis, 2 with prominent lenticulostriate collateral vessels, and 1 with a
hypoplastic arterial segment.

Hydroxyurea effects. The age, baseline laboratory characteristics, and pre-treatment

TCD values for the 37 children with increased flow velocities who enrolled in the
prospective study are included in Table 1. Their pre-treatment laboratory values were
very similar to those reported in the HUG-KIDS trial [19]. The average pre-treatment TCD
velocities were highest in the MCA, followed by ACA and then PCA vessels, but no
significant differences were observed between the right- and left-sided vessels.
All 37 children were treated with hydroxyurea and eventually reached a stable
MTD of 27.9 2.7 mg/kg/day (median 28.6, range 18.8 to 32.6 mg/kg/day). Compliance
8

with hydroxyurea therapy was estimated to be excellent for most of the patients, although
six children (16%) had presumed poor medication adherence based on hematological
parameters and failure to attend clinic appointments regularly. Laboratory values at
hydroxyurea MTD for the entire cohort of 37 patients illustrate the expected significant
increases in hemoglobin concentration, hematocrit, MCV, and %HbF (Table 1).

TCD Changes. Follow-up TCD screening was performed on 36 children after reaching
hydroxyurea MTD, with an average interval of 10 5 months (median 8 months) of
therapy. The results of these follow-up TCD examinations demonstrated a significant
decrease in the maximal TCD flow velocities, for either the MCA or ACA vessels (Table
1). Follow-up TCD examination was not obtained in one non-compliant patient, who was
lost to follow-up 14 months after initiating hydroxyurea treatment.
The magnitude of the decrease in TCD flow velocity was significantly associated
with the baseline TCD velocity. Figure 1 illustrates that children with the highest baseline
TCD velocity measurements had the greatest decrease in response to hydroxyurea
therapy (r2 = .12, p = .04). The decline in TCD flow velocities observed in association
with hydroxyurea therapy at MTD was then compared to the corresponding increases in
hematocrit for each patient. There was no correlation between the magnitude of the TCD
decrease and the hematocrit increase (r2 = .06, p = .17), but on average the median TCD
velocity decreased 4.8 cm/sec for every percent increase in hematocrit (data not shown).
An additional TCD examination was then attempted at least 1 year after reaching
MTD, to determine if the effects of hydroxyurea treatment were sustained. A total of 28
long-term follow-up TCD studies were performed at an average of 25 7 months (median
24 months) after starting hydroxyurea therapy. In almost every case, the TCD velocity
9

was similar to the initial follow-up study (Figure 2), with an average further decrease of 12
15 cm/sec (median 10 cm/sec decline, p = NS).
Outcome of initial conditional and abnormal TCD velocities. Fifteen children had
conditional baseline TCD flow velocities, including 8 with low conditional values (170184 cm/sec), and 7 with high conditional values (185 -199 cm/sec). Upon reaching
hydroxyurea MTD, 14 of 15 children had decreased TCD velocities with only 3 low
conditional studies on follow-up examination, and none at long-term follow-up. One child
with an initial left MCA flow velocity of 166 cm/sec (baseline HbF = 10.0%) had an initial
decline after 11 months of hydroxyurea therapy to 147 cm/sec (HbF= 14.9%), but after 20
months of hydroxyurea therapy with suspected non-compliance (HbF= 11.4%) the flow
velocity had increased again to 171 cm/sec.
The six children with initial abnormal TCD flow velocities had relatively large
decreases in TCD flow velocities in association with hydroxyurea therapy. The TCD
values for the 8 vessels with initial abnormal values decreased from 216 14 cm/sec to
173 31 cm/sec (p<.001). One 5-year-old male with a conditional TCD but admitted
hydroxyurea non-compliance had conversion to an abnormal TCD; the right MCA
remaining unchanged at 171 cm/sec, but the left MCA increased from 167 to 234 cm/sec
and the right ACA increased from 100 to 221 cm/sec. Hydroxyurea was discontinued for
this child and he was changed to monthly blood transfusions.
One new neurological event occurred in a 14-year-old female with abnormal TCD
after 7 months of hydroxyurea therapy. The overall incidence of new neurological events
for the entire patient cohort during treatment was 1 in 193.2 patient-years of follow-up, or
0.52 events per 100 patient-years of observation.

10

DISCUSSION

Despite the definitive results of the STOP and STOP 2 trials, there are several
unresolved issues regarding TCD flow velocities and stroke risk in children with SCA.
First, the positive predictive value of an abnormal TCD result for stroke is relatively low,
since only one-third of children with abnormal TCD velocities and even fewer with
conditional TCD velocities will develop an overt clinical stroke [8,9]. Long-term follow-up
from the original STOP trial has also identified a subset of patients who remain strokefree off transfusions despite persistent abnormal TCD flow velocities, and also some
transfused patients who continue to have abnormal TCD velocities [20]. Discordance
between TCD and brain MRI/MRA results is also recognized, including the observation
that most children with abnormal TCD velocities will have no abnormalities on brain MRI
or MRA [21,22]. In addition, there are well recognized risks of blood transfusions,
including iron overload and alloimmunization, for children with SCA receiving indefinite
monthly transfusions in accordance with current NHLBI recommendations for abnormal
TCD velocities. In the STOP trial, 10 of 63 subjects randomized to the transfusion arm
developed new RBC alloantibodies, despite extended phenotypic matching of blood, 5
required central line placement to facilitate transfusions, and almost all of the patients had
increases in serum ferritin to the range requiring initiation of iron chelation therapy [23,24].
Finally, the projected costs of chronic blood transfusions (including chelation therapy)
approaches $400,000 per patient decade [25]. Taken together, these observations
suggest that an alternative and effective treatment for primary stroke prevention would be
a useful option for patients with SCA and an abnormal TCD velocity.

11

Although monthly transfusions are currently recommended for children with

abnormal TCD velocities, the mechanisms by which transfusions reduce stroke risk have
not been fully elucidated. Acutely, transfused erythrocytes quickly raise the circulating
erythrocyte mass and increase the hematocrit with concomitant increased blood viscosity,
and have been demonstrated to lower the TCD velocity within 30 minutes of starting the
transfusion [26]. Chronic transfusion therapy also directly inhibits erythrocyte sickling,
improves blood rheology, reduces red cell adhesion, and lowers the plasma-free
hemoglobin and other laboratory evidence of hemolysis [27-29]. Similar effects are
observed in association with hydroxyurea therapy, which also increases the hematocrit,
inhibits erythrocyte sickling by increased fetal hemoglobin, improves red cell rheology,
reduces red cell adhesion, and lowers LDH and total bilirubin concentrations [19,30-32].
Both transfusions and hydroxyurea therapy might, therefore, be expected to lower TCD
flow velocities in children with SCA. In the setting of secondary stroke prevention,
hydroxyurea therapy has been shown to provide similar protection as transfusion
prophylaxis [33,34].
Gulbis and colleagues [15] recently reported updated results from the Belgian
registry, which included 34 children with SCA at risk for primary stroke on the basis of an
abnormal TCD. Although these patients were treated with hydroxyurea below MTD
(median dose <20 mg/kg/day), 11 children with serial TCD measurements had a
significant decrease in TCD velocities from 235 25 cm/sec to 204 27 cm/sec (p<.01).
Only 1 of the 34 children developed a new neurological event over 96 patient-years of
follow-up. In contrast, our Phase II trial provides the first prospective data focused
specifically on the ability of hydroxyurea therapy to lower TCD velocities in children with
SCA. In 37 pediatric patients with increased TCD flow velocities 140 cm/sec,
12

hydroxyurea therapy significantly lowered the TCD values and this effect was sustained
for at least one year after reaching MTD. Children with conditional TCD velocities had
improvement, with resolution of the conditional velocities at long-term follow-up in 14 of
15 children. Compliance with hydroxyurea remains a concern, however, since those
children with poor medication adherence had minimal TCD responses, and one
admittedly non-compliant child had conversion from conditional to abnormal flow
velocities, leading to a change in therapy with chronic transfusions. The long-term risks
of hydroxyurea also remain undefined for young patients with SCA.
These data do not demonstrate definitively that hydroxyurea is an efficacious or
effective treatment for the prevention of primary stroke in children with SCA. Although
most of the children with increased TCD flow velocities in this study had a significant
decrease in the TCD values while on hydroxyurea therapy, there was one new
neurological event in a child with an initial and follow-up abnormal result. A controlled
multicenter trial is needed to determine the efficacy of hydroxyurea therapy to lower TCD
velocities and ultimately, to prevent primary stroke in children with abnormal TCD flow
velocities.
ACKNOWLEDGMENTS

This study was supported by NHLBI grants 5K23HL4005 (SZ) and K24HL068230 (RW).
SZ designed and performed the study, and wrote the paper; WS, SB, and NB enrolled the
patients and performed the study; RW designed the study and wrote the paper. The
authors also acknowledge the efforts and support of Dr. Daniel Laskowitz for assistance
with TCD examinations, Jacqueline Davis and Tracey Kelly for clinical care, and Matthew
Smeltzer for statistical assistance.
13

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18

Change in TCD Flow Velocit y ( cm/ sec)

70

60

50

40

30

20

10

0
14 0

1 60

1 80

2 00

2 20

2 40

2 60

Maximum Baseline TCD Flow Velocit y ( cm/ sec)

Figure 1. The decrease in TCD flow velocity on hydroxyurea at MTD is correlated with
the maximal baseline TCD flow velocity. The magnitude of the decline in TCD flow
velocity (shown on the y-axis in absolute value) was significantly correlated to the
maximal baseline TCD flow velocity (r2 = 0.12, p = .04).

19

Maximum TCD Flow Velocit y ( cm/ sec)

24 0
22 0
20 0
18 0
16 0
14 0
12 0
10 0
80

Baseline
173 + 22

MTD
141 + 22

Follow-up
129 + 20

Figure 2. Long-term effect of hydroxyurea therapy on TCD flow velocities. Children with
SCA and increased baseline TCD velocities received hydroxyurea therapy at MTD. The
maximum TCD velocity is shown after reaching MTD and then in long-term follow-up for
28 children. There was a significant decrease from baseline TCD flow velocities to the
MTD values (p<.001), and this decrease was sustained at long-term follow-up.

20

Pre - Hydroxyurea

Hydroxyurea at MTD

Mean 1 SD

Median

Mean 1 SD

Median

p-value

Age (years)

6.8 3.5

5.6

7.6 3.2

6.8

Hb (gm/dL)

7.8 1.1

7.8

9.4 1.0

9.4

<.0001

Hematocrit (%)

22.5 3.3

22.0

26.8 3.0

26.5

<.0001

MCV (fL)

86 8

88

104 9

103

<.0001

HbF (%)

10.3 6.6

9.9

22.7 7.9

23.3

<.0001

R MCA (cm/sec)

166 27

162

135 27

134

<.0001

L MCA (cm/sec)

168 26

166

142 27

144

<.0001

R ACA (cm/sec)

130 25

127

110 33

98

.0057

L ACA (cm/sec)

132 29

133

113 29

114

.0078

R PCA (cm/sec)

85 30

87

76 23

78

NS

L PCA (cm/sec)

91 29

90

73 24

77

.0061

Table 1. Laboratory parameters and TCD flow velocities for 37 children with SCA, before
hydroxyurea therapy and after reaching MTD.

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