Transcranial Doppler (TCD) Ultrasonography in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial.
Authors: Wang Winfred , Rees Renee C , Miller Scott T. , Brown R. Clark , Casella James F. , Iyer Rathi V. , Kalpathi Ram V. , Luden Judy , Rogers Zora R. , Thornberg Courtney , Adams Robert J. , Pavlakis Steven ,   the BABY HUG Investigators
Published: April 2020

Abstract
Introduction: Transcranial Doppler ultrasound (TCD) is used in children with sickle cell anemia (SCA) to detect stroke risk. TCD screening is mostly employed in children between 2–16 yrs of age; its use in infants &lt;2 yr of age is less well established. BABY HUG is an NHLBI-NICHD sponsored Phase III clinical trial in infants with SCA comparing hydroxyurea (HU) to placebo to ascertain efficacy of HU in preventing damage to the spleen and kidney (NCT00006400). As a secondary endpoint in this trial, TCD was done to determine possible effects of HU in babies with SCA. We reviewed the baseline TCD data of infants obtained during eligibility screening in BABY HUG.
Methods: All subjects underwent a baseline TCD using the Nicolet Companion (EME) 2-MHz pulsed Doppler. All infants were 7–17 months of age during screening, had no history of stroke and were not receiving chronic blood transfusion. Blood flow velocities were recorded using the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol with the exception of reducing the standard sample volume to 4 mm. No sedation was used. The time averaged maximum mean velocity (TAMM) was measured to determine the highest velocity on either side to categorize the study as normal (highest velocity &lt;170 cm/sec), conditional (170 – 199) or abnormal (≥200). Recordings of both middle cerebral (MCA) and internal carotid (ICA) arteries defined an adequate TCD. Eligibility for BABY HUG required at least an attempted TCD. TCD exams were read by blinded reviewers at the Medical College of Georgia and results transmitted to Clinical Trials & Surveys Corp. for statistical analysis.
Results: TCD exams were attempted on 204 infants. Six exams were unsuccessful (no data) because of the subjects’ lack of cooperation and 11 TCD’s were inadequate. Of the remaining (187) TCD exams, 183 were normal and four included at least one conditional velocity. No subjects were found ineligible for the trial due to an abnormal TCD result. The mean velocity of the left MCA was 114.0 cm/sec ± 22.1 and that of the right MCA was 111.7 cm/sec ± 23.1. The top two deciles of the maximum TAMM reading for each child were 149 cm/sec and 141 cm/sec. Both age and total hemoglobin (Hb) were significantly associated (p&lt;0.0001) with the mean MCA velocity in a multiple regression model. Analysis of the maximum TAMM for each child versus age, total Hb, Hb F, reticulocyte count, and Bayley Scales of Infant Devlopment II in a multiple regression model showed that only age (positively, p=0.0001), reticulocyte count (positively, p=0.015), and total Hb (negatively, p=0.0025) were significantly associated with the maximum TAMM.
Conclusions: Adequate baseline TCD evaluation was obtained on 187 of 204 (92%) subjects. All but 4 were normal by STOP criteria as compared to approximately 10% abnormal and 18% conditional in STOP screening of older children. Using multivariate analysis, baseline TCD velocities varied inversely with the degree of anemia, as expected, but in addition varied directly with age The lack of significant TCD abnormalities is interesting, given the presence of silent infarcts in 13% of this group of children (Pediatr Blood Canc, 2008). When post-treatment TCD data collection is completed, it may become apparent whether:
lower TCD velocities reflect a lack of stenotic vascular disease in infants; infants with TAMMs in the upper deciles will be more likely to have abnormal/conditional velocities as they grow older; and HU will have an impact on TAMM.